8 replies to this topic

[Trey]

Sprycel is the "most different" of the TKI drugs.  It binds in a different way than both Gleevec and Tasigna, it acts against both active and inactive forms of BCR-ABL, and it inhibits the SRC family of kinases unlike the others.  More recent studies have also shown how Sprycel stimulates mobilization of lymphocyte cells (T-cells, B-cells, NK-cells).  This is believed to provide more opportunity for the body to fight leukemia as the leukemic cells are exposed to more lymphocyte WBCs.

http://ash.confex.co...Paper28481.html

http://ash.confex.co...Paper30844.html

[jrsboo]

Ok Trey,

I read them.  But even after googling all the words I didn't know, I don't completely understand.  Sprycel stimulates lymphocyte production.......but is that a good thing or a bad thing?  Oh Grand Poobah of all that is CML..........please enlighten us padewans if you can..........

Caroline

[Trey]

It is a good thing when it comes to fighting leukemia.  When I said "This is believed to provide more opportunity for the body to fight leukemia as the leukemic cells are exposed to more lymphocyte WBCs", I meant that more lymphocyte WBCs (T-cells, B-cells, NK-cells) will look at the leukemic cells and question their right to be in the body.  If they decide the leukemic cells should be killed, the killer cells will do the deed.  So if Sprycel causes additional lymphocyte WBCs to float around in the blood looking for something to kill, then the liklihood of leukemic cells being seen as abnormal and killed is increased.  This means that Sprycel has a very similar effect as Interferon in fighting CML.  By itself, the increased lymphocyte WBCs are not normally enough to fight the leukemia.  But combined with the anti-BCR/ABL activity that TKI drugs have, this makes Sprycel more potent.  Sprycel also inhibits the SRC kinases, which can be used as a back door survival mechanism for leukemic cells.  So overall, this shows why Sprycel can be so effective against CML, since Tasigna and Gleevec do not mobilize the lymphocyte WBCs as Sprycel does.

[jrsboo]

Thanks Trey,

This leads to my next question.

While I understood that the TKI's were inhibiting the production of the immature (non normal) WBC, I don't understand how that works to reduce the BCR-ABL activity.  I thought that the Sprycel was just stopping the bone marrow from producing the wrong wbcs.   But that the translocation of the Philadelphia syndrome was still occuring.  It seems though, that if one is to get to cytogenic and the MMR response, it would mean that the translocation was no longer occuring. 

Is that right?  And if so, how are the drugs doing that?

I don't really expect you to know all of this.  But thought I would give it a try.  You do have such a grasp on all of this, it is quite amazing. 

I think that I am just starting to deal with the life long aspect of it all.  These first 3 months seem to have been a huge amount of effort expended into finding the best oncologist, finding the best treatment, finding the best way to express what I need to the cancer centers, finding which side effects I should complain to the dr. about, and now that I have some exposure, it is getting emotionally scary to think that this new normal is going to last for 30 more years.  Quite an adjustment. 

Caroline

[Tedsey]

I got a little nervous there after I read your title.  Nice to read that it may be really good news!  Sprycel, so far, has been a life-changing drug for me.

[GerryL]

Hi Trey,

Probably a dumb question as I haven't looked at Sprycel discussions, since the process in Australia is to put you on Glivec initially, then move you onto one of the other TKIs if there are any issues. Can't complain, these medications are heavily subsidised in Australia.

But do they think there is a possibility of Sprycel being able to attack the leukemic stem cells that Glivec and Tasigna can't reach?

[Trey]

Caroline,

Your questions:

"While I understood that the TKI's were inhibiting the production of the  immature (non normal) WBC, I don't understand how that works to reduce  the BCR-ABL activity.  I thought that the Sprycel was just stopping the  bone marrow from  producing the wrong wbcs.   But that the translocation  of the  Philadelphia syndrome was still occuring."

The TKI drugs turn off the ABL found in the BCR-ABL which is in the leukemic cells, which in turn confuses the leukemic cell, and it shuts down and dies.  It does not stop the high level leukemic stem cells from producing new leukemic cells (the stem cells are believed to be immune to TKI drugs), but it shuts down and kills those leukemic offspring that are produced by the leukemic stem cells.  So the leukemic stem cells keep producing, and the TKI drugs keep killing.  It is a matter of population control through execution, not preventing the procreation by the stem cells.

"It seems though, that  if one is to get to cytogenic and the MMR response, it would mean that  the translocation was no longer occuring."

The translocation occurs once at the beginning of the leukemic process.  At that point we had one leukemic stem cell.  After that the offspring of that one cell all have the leukemic transloction.  This will be the case until the disease is cured (some day).

Gerry,

Sprycel attacks higher level leukemic cells than Gleevec or Tasigna.  This is believed to be due to its ability to inhibit the SRC family of kinases.  Those higher level leukemic cells are senior progenitor cells, and probably not actually stem cells.

http://community.lls...age/24653#24653

[GerryL]

Thanks Trey - I'l have to keep my fingers crossed for a while longer waiting for a cure - at least they are getting closer to the start of the chain reaction.

[jrsboo]

Trey,

YOU ARE AWESOME.  Thank you so much for putting into english for me.  I actually understand (after reading through 3-4 times)!!!

Caroline