12 replies to this topic

[jwbwater]

Hi all,

I have been reading the posts here for a couple months, but have only posted a couple times.

I'm hoping someone here might be able to shed some light on the cytogenetics from my last bone marrow biopsy.

Cytogenetics/FISH: -Positive FISH study for BCR/ABL1 fusion
-Complex abnormal male karyotype:
46,XY,inv(3)(q21q26.2),t(9;22)(q34;q11.2)[8]/46,sl,del(7)(q22q34)[6]/
46,sl,inv(7)(q22q36)[5]/46,XY[2]

So what I believe this means is that they looked at 23 cells and found 4 genetically distinct populations:

8 cells had two mutations:
inv(3)q21q26.2)      (I believe this has something to do with an enzyme called EVI1)
and
t(9;22)(q34;q11.2)  (This is the Philadelphia chromosome)

6 cells had del(7)(q22q34)

5 cells had inv(7)(q22q36)

and 2 of them were normal health cells (yay, I still have some normal cells!)

Two things:
1.  Two of these populations are reported starting with 46,XY and the other two with 46,sl - any idea what sl means?

2.  I would like to know more about the two mutant populations that do not have the Philadelphia chromosome.  It is not clear to me that there is any reason to expect them to respond to tasigna since it inhibits the mutant tyrosine kinase coded for by the Philadelphia chromosome.  I did some searching for them on the web and didn't find a whole lot although I believe one of them is associated with myelodysplastic syndrome (MDS), sometimes called pre-leukemia.

I would appreciate any light you could shed on this.

Jim

[Trey]

Jim,

First, "sl" is an abbreviation for "stemline" that simply means "the following cells have all the abnormalities listed in the previous line plus the following additional ones".  Sort of like using "ibid" for footnotes in a term paper.

The first karyotype is:

46,XY,inv(3)(q21q26.2),t(9;22)(q34;q11.2)[8]

Which means that 8 cells (as shown by the [8] ) showed:

46: human

XY: male

inv(3)(q21q26.2): Chromosome 3 has an "inversion" whereby a piece broke off, inverted itself (flipped 180 degrees) and then re-attached backward.

t(9;22)(q34;q11.2): these cells have the Philadelphia Chromosome

So these 8 cells showed the Philadelphia Chromosome and also an inversion of genes in Chromosome 3.

The second karyotype is:

46,sl,del(7)(q22q34)[6]

Again, 46 = human.  Then the "sl" is like using "ibid.", and means that the originally listed genetic screw-ups apply here also, but then it adds more.  So "sl" means it also has the 46,XY,inv(3)(q21q26.2),t(9;22)(q34;q11.2) as in the first karyotype; but then also adds the del(7) at the (q22q34) location.  This means that you are missing a piece of one of the two copies of the Chromosome 7.  You also have the Chromosome 3 inversion plus the Philadelphia Chromosome in these 6 cells.  The del(7)(q22q34) can be associated with myeloproliferative diseases as a secondary genetic mutation, but its impact is not always clear.  Sometimes it does nothing.

The third karyotype is:

46,sl,inv(7)(q22q36)[5]

Another "sl" means that the original genetic screw-ups are also in these cells, so these ones have the 46,XY,inv(3)(q21q26.2),t(9;22)(q34;q11.2), but then they also add another acrobatic genetic mutation called inv(7) whereby the chromosome 7 has an inversion (180 degree flipped genes) at section (q22q36) in 5 cells.  So whereas in the second karyotype showed 6 cells with a partial deletion of Chromosome 7,  these 5 cells do not have that partial deletion, but rather have an inversion of genes on chromosome 7.

46,XY[2]: Two cells show normal human male (don't take that too literally).

What does this all mean?  If the TKI drugs work well, it may not mean much.  But any time there are unusual karyotypes such as these, a true CML specialist should be consulted.  To me, one of the best in such cases is Dr Talpaz at Univ. of Michigan.  I would suggest you email or call him, or have your own Onc contact him if you prefer that approach.

http://www2.med.umic...rtment=Internal

[PhilB]

Hi Jim,

That's an impressive set of cytogenetics!  You haven't been using too much Benzene to clean out your nuclear reactor have you?

I've only a couple of things to add to Trey's masterly exposition:

1. The good news is that all the weird and wonderful cells are Ph+. Knock out these cell lines via TKI therapy aimed at the 9:22 translocation and you've got rid of all the other mutations too.  You even have a nice population of healthy cells standing by to take over.
   
2. Don't hesitate to contact someone like Dr Talpaz as Trey suggests because they will be really interested to hear from someone with such a weird and wonderful collection. 
   

Phil

[jwbwater]

Trey, PhilB,

Thanks for the replies.  It's good to know that all the mutant cells are Ph+

I'll email Dr. Talpaz and let you know what he says.  I did email Dr. Druker this bone marrow biopsy report, but I'm not sure how close he looked at it.  I just asked him the mundane Tasigna vs Sprycel question given that I have no point mutations on the oncogene.  His reply was that it's basically a toss up, but he would have gone with sprycel.  In addition he said that his guess is that neither is likely to provide a long term solution for me, but rather act as a bridge to transplant.  For now I'm going to go ahead and hope he's wrong about that last point.

As for my "impressive" cytogenetics, I do work in an organic chemistry lab and work with some fairly nasty stuff, but no benzene and as a survivor of childhood Hodgkin's disease, I have a history of chemotherapy so the issue is a bit clouded.

Thanks again for the replies.

[Tedsey]

Jim,

I don't have anything to add.  I just want you to know that you are in my thoughts.  I also want Dr Druker to be wrong.  Hopin' all the best for you.

Tedsey

[reedgirl]

Jim,

  I too don't have much to add but would also just encourage you to contact Dr. Talpaz.  My husband also had a complex karaotype from his bmb.  Trey advised us to contact Dr Talpaz.  I called the number that I located on the internet, his secretary asked me to fax my husbands bmb and send a follow up email with my contact information to the dr himself. I did that and the same night he emailed me with his phone number to call, which I did the next day.  He answered the phone and was very interested in seeing my husband and taking him on as a patient.  With in one week we were headed to Michigan for the first appointment.  I really like and trust Dr Talpaz.  You will not be sorry or have any regrets in contacting him to look at your report.

  Best of luck to you and keep us posted on how you make out with your progress.

Audrey

[jwbwater]

Tedsey, Audrey,

Thanks for the positive thoughts.  I did email Dr. Talpaz and his advice was similar to Dr. Druker's.  Switch to sprycel to obtain remission and then transplant.  Woof.  I'll have to talk this over with my doctor tomorrow.  He's had me on Tasigna for five weeks and I don't yet know if it's working better than Gleevec.  On the plus side, I started seeing a naturopathic oncologist and he mentioned that there is research showing that high cellular expression of efflux pumps (likely the case for me since I had chemo for Hodgkin's disease 20 years ago) reduces the effectiveness of Gleevec, but for some reason does not appear to affect Tasigna so I'm still holding out hope for a good response to Tasigna.

[reedgirl]

Wow Jim...why jump to a transplant?  So how long are you to take Sprycel? If you need the transplant no matter what they why not just go right to that?  Guess I don't understand all about your case, but that seems so extreme so quick.   Praying the Sprycel works for you and you are able to reach and retain remission.

Audrey

[jwbwater]

The bone marrow biopsy that showed the complex cytogenetics also showed 21% blasts and blast equivalents and that was just 11 months after diagnosis (4% blasts at diagnosis) so it looks like my brand of CML is a bit on the aggressive side.  The doctors are anticipating that if I get a response to Tasigna or Sprycel it will be transient rather than long lasting so best to have a transplant lined up so if the response starts to go away we're ready to go. 

The upside right now is I feel great (at least today).  My Tasigna side effects are either becoming less intense (heart palpitations, back pain) or I've figured out how to deal with them (insomnia).  So I'm doing my best to stay positive and wait to see how the test results come out. 

[Trey]

Jim,

I did not want to jump ahead previously, but what Dr Druker and Dr Talpaz see is that this could be more than CML, maybe Ph+ AML or Ph+ ALL leukemia* rather than purely CML.  If so, the drugs may work for a while, but then can stop working after a relatively short time.  The del(7)(q22q34) is the problem here, because it can make the disease worse, although it does not always do so.  It is a tricky business trying to figure out what some of these chromosome abnormalities can cause.  Often it is a wait and see approach.  But your increased blast count while on TKI drugs is not a positive sign.  But if Tasigna or Sprycel can reverse this issue (and I would switch to Sprycel) then there is still a chance that the TKI drugs could work.

Whether your previous chemo led to this or not cannot be known for certain.  But it is definitely among the possibilities.

A Flow Cytometry test may be able to shed some additional light on what is happening with your white blood cells.  I would suggest discussing this with your Onc.

* Ph+ : Philadelphia Chromosome positive

[jwbwater]

I've wondered about my diagnosis myself since previous chemotherapy typically predisposes people to AML rather than CML, but both hematologists I've seen agreed that my bone marrow biopsy at diagnosis merited a CML diagnosis though they did not disclose how they came to this conclusion.  The reading I've done implicates the inv(3)(q21q26.2) mutation as a borderline case for AML/CML diagnosis:

http://ash.confex.co...Paper23540.html

After getting the most recent bone marrow biopsy result my current hematologist said that my situation is now clinically equivalent to AML.

It's interesting that even the transplant specialist I saw (who seems more well read than either of the hematologists I've seen) wanted to give Tasigna a chance to work, and he agreed with the use of Tasigna over Sprycel though his reasoning seemed to be based primarily on side effects.

The flow cytometry section of my most recent bone marrow biopsy report says:

Flow cytometric analysis of bone marrow aspirate shows increased atypical myeloid blast (8%) with increased immature monocytic cells/monocytic precursors (12%) and decreased maturing myeloid cells.  Review of a current aspirate smear shows increased blasts and blast equivalents (~20% of overall marrow cellularity).  The patient has a known history of CML with increased blasts.  These findings are compatible with impending blast phase of a previously diagnosed chronic myelogenous leukemia.  Suggest correlation with morphologic, cytogenetic and molecular studies.

[PhilB]

Hi Jim,

Even without the possibilities mentioned by Trey that it is really Ph+ something else rather than CML, that blast number looks like a game changer.  As Trey says, the TKI's may work, and it's good to have them as a fallback position if you can't find a good donor, but if you're playing the percentages then transplant would normally be the route of choice for someone with 20%+ blasts.  I hope they find you a good match, you have a nice boring transplant and that you keep us all posted on how it goes.

Best wishes

Phil

[jwbwater]

Thanks for the positive thoughts Phil, I appreciate it.

Jim