Hello and I hope everyone is having a great start to 2024.
There has been much discussion here and elsewhere re CYP3A4 and its importance in metabolizing TKIs. However, I am finding it difficult to gather information on CYP3A5.
Based on tests from last Sept/Oct, my 3A4 showed Neg/Neg, which "predicts normal metabolizer phenotype."
However, my 3A5 showed *3/*3 - which "predicts the poor metabolizer phenotype." This appears to be one piece in the puzzle why I, and perhaps others, suffer from severe myelosuppression for a standard dose of TKI. (Undoubtedly there are other reasons why some are poor metabolizers.)
A specialist I am working with agrees that poor 3A5 can have an effect on the 3A4.
Indeed, one study I found describes this.
From: Inhibition and induction of CYP enzymes in humans: an update
https://link.springer.com/article/10.1007/s00204-020-02936-7
"The evaluation of induction phenomena of CYP3A enzymes is complicated by the closely related CYP3A5 enzyme. CYP3A4 and CYP3A5 have widely overlapping substrate specificities and their regulation shares certain features such as crucial role of PXR and CAR (Burk et al. 2004). A notable difference is the extensive influence of genetics on CYP3A5 expression."
The paper also goes on the state: "The CYP3A5*3 allele with severely decreased enzymatic activity is more common than the CYP3A5*1 allele (CYP3A5*3 allele frequency is ~ 90% in Caucasians and 50% in African–Americans) (Lamba et al. 2002). Thus, most Caucasians do not have a functional CYP3A5 enzyme."
If this is the case, then how is it that some CMLers can take a standard dose of TKI and NOT suffer myelosuppression? And how is it that others are less fortunate?
The current protocol I am doing right now is a fractional dose of a TKI. The goal, as the specialist informed me, is NOT about TFR or even MMR. Rather, the goal is to place just enough pressure on the CML stem cells but keep the bone marrow in such a state I do not suffer from low cell counts (red, white, and platelets) - a condition known as pancytopenia, something I unfortunately know all too well.
Anyone who has extensively researched stem cell transplants on CML patients should respect and fear Graft vs Host Disease (GVHD). It does not matter even if the HLA match is a "perfect" 10 out of 10. GVHD, for some, can be serious enough that they are trading one form of hell for another. This is a gamble I want to avoid.
So my question is, are there others out there who have or currently wrestle with something similar? I would very much like to share best practices, theories, anecdotal knowledge, and studies.
@scuba - I recall you mentioning going off TKI for approximately 3 months due to myelosuppression. Your thoughts are greatly appreciated.
There are other very smart people on this thread and I hope to hear from you as well.
Thank you