5 replies to this topic

[kat73]

It has been stated that Tasigna is the best bet if you're concerned with the side effect of puffy eyes (periorbital edema).  Is this so?  And, if so, why?  What are the differences in the off-target kinase inhibition profiles between Sprycel and Tasigna, for instance?  I'm trying to decide whether to lobby for switching, and I need a solid scientific rationale.  Is there one?

[Trey]

The ties between inhibiting specific kinases and side effects is only known by cause and effect.  It is not known precisely which inhibited kinases cause side effects.  A few are speculated, but very few are certain.  Here is a good article on the subject:

http://www.nature.co...eu2009111a.html

 

But we know that Gleevec causes quite a bit of body edema, which may be caused by c-Kit and/or PDGFR inhibition.  Tasigna inhibits c-Kit and PDGRF to a lesser degree, which we know because it does not work as well for GIST patients who require the c-Kit inhibition as a therapy.  One might speculate inhibition of c-Kit has something to do with edema, as well as PDGFR, but that is not certain. 

 

The best method is to try the drug and see what happens.  That may not always be possible due to Onc and insurance issues, but it the only "scientific" way o know what will happen.

[kat73]

Thanks for the article, Trey.  I read it carefully (and slowly!)  I did not see any mention of the fatigue and asthenia (a new word I came across recently - in the side effects list for the various TKI's - for the phenomenon of feeling muscle weakness) in this discussion of the various off-target inhibitions.  And yet it is one of the most frequent and universal complaints I see here on the discussion board.  I get what you said about cause and effect, but I wonder if you would care to speculate as to what is it in all the TKI's that seems to "cause" the fatigue and muscle weakness?

[Trey]

Matching precise side effects to specific kinase inhibition is difficult.  Off-target inhibition varies for each drug.  All inhibit ABL (in the BCR-ABL and also in free form).  The kinase inhibition profiles of each of the three top TKI drugs is as follows:

Gleevec: 9

Tasigna: 22

Sprycel: 38

http://onlinelibrary...1/gtc.12022/pdf

 

But the numbers do not tell the whole story, since they all inhibit the kinases to differing degrees at different drug concentration levels. 

 

Here is a good overall side effects presentation about TKI drugs:

http://www.mpdmeetin...jenny_byrne.ppt

 

More stuff:

http://erc.endocrino...2-0400.full.pdf

[kat73]

Thanks very much, Trey.  Very interesting reading.  It was nice to note from the ENRICH study that, in switching from imatinib to nilotinib periorbital edema was resolved in 80% patients.  Face edema resolved in 50% of patients who switched and fatigue in 33% (and fatigue improved - not resolved but improved - in 25%.)  When you look at the chart showing the distribution of off-target kinases for the five CML drugs, I totally get what you are saying:  they all hit them all to differing degrees and points.  And it's a guessing game as to how that translates to side effects. 

 

I have another question.  It sounds simple, but it's not really, if you think about it.  How does reducing dosage help with side effects?  Assuming you are delivering a therapeutic dose for CML and your PCR shows stability or improvement, then the drug must be reaching all the targeted cells and doing its work in all those cells.  If you assume that, then the off-target hits happen right along with the drug, right?  So why should the side effects from those off-target inhibitions be any less?  I'm trying to decide whether to ask to reduce dosage or switch to another TKI.

[Gail's]

Really like the Jenny Byrne presentation, Trey. Thanks for posting it.