Hello everyone,
After my strange experience with Nilotinib, I feel much better on Asciminib now, I did some research on the metabolic syndrome and its components, which led me to the connection between chronic inflammation and CML, of which I was not aware, so I put some interesting papers I’ve read together in the form of summaries and links.
You may find it interesting, as for me it opened new perspectives on CML origin, operations and survival methods, TKI non-mutation related resistance, and potential ways to improve TKI response and even inhibit CML without necessarily eradicating LSCs.
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Note: Please be aware that I’m not advising or recommending anything as I have no medical education.
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From what I’ve read so far, I have strong impression that chronic inflammation plays important role in CML even after we achieve deep response on TKI. The researchers basically suggest that one way to impair CML is through suppression of chronic inflammation which then allows the immune system to heal itself.
They think that it’s technically impossible to eradicate CML completely and the only way to overcome it is by reactivating the immune system, which initially became dysfunctional most likely due to the prolong exposure to chronic inflammation.
There is a set of pro-inflammatory cytokines which are specific to CML. These promote CML survival and progression, deactivate P53, disable NK cells causing loss-of-function, activate NF-kB which drives CML etc, basically creating a thriving environment for CML survival. These cytokines are most likely released by non-CML immune system cells.
The researchers suggest that the immune system can heal itself once the chronic inflammation is suppressed, I think Interferon treatment was also about fixing the immune system, and it can be achieved to a certain extent using lifestyle modifications and natural anti-inflammatory agents such as anthocyanin, curcumin, quercetin etc.
The right food and regular exercise, but non-intensive, are critical here and no amount of supplementation can offset that.
There are many documents about these natural agents killing CML cells, but the plasma concentrations achievable through supplements are 1000+ times below the effective levels, so I didn’t focus on those lab specific results. However, these can measurably suppress inflammatory cytokines even at lower doses.
Suppression of chronic inflammation may be interesting for those who hit BCR-ABL plateau or have been oscillating within a range up and down. It’s important to find the effective TKI and get as deep in MMR as possible, then these additional interventions may actually help by recovering immune system.
I also looked into and discussed with my doctor the so called “emerging new clones” and their potential link to TKI resistance. These are known as “clonal evolution” or “additional chromosomal abnormalities” and are basically the results of new chromosomal translocations, other than CML Ph+ (9-22), e.g. it could be 8-47 or something else. However, these either do not manifest as they are equally susceptible to TKI as 9-22 ones, or they are fully resistant and rapid progression follows, which is reflected in rising BCR-ABL numbers. So just as mutants, some are inactive and other are fully resistant, clonal evolution is probably not behind the cases when the BCR-ABL is more or less stable, but it stopped decreasing.
Before this research, I also researched the long list of known signaling pathways on which CML depends and how to naturally inhibit these and activate P53 - which seems to be off and non-mutated in CML CP. Here I freaked out early on when I realised that most of the popular supplements activate anti-P53 pathways such as SIRT1, however it turned out that this is true only in non-cancerous cells while in cancerous ones polyphenols and antioxidants actually suppress these so called “rejuvenating pathways” and activate P53, so what actually happens depends on the state of the affected cell. They still may interfere with TKIs in some way, so always best to check with your doctor.
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The only supplement that I know of that may decrease TKI effectiveness is NAC, but even this was proved in lab only. Here is a couple of a bit cryptic documents that discuss these issues found during lab research.
Antioxidant and Oncogene Rescue of Metabolic Defects Caused by Loss of Matrix Attachment
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931797/
Effects of antioxidants on apoptosis induced by dasatinib and nilotinib in K562 cells
https://pubmed.ncbi.nlm.nih.gov/29345355/
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If you google “curcumin asciminib interaction” there should be a summary under DrugBank link saying “The serum concentration of Asciminib can be increased when it is combined with Curcumin.”, but I don’t have access to the database so cannot look further for source, still be aware of potential interaction and always discuss with your doctor.
Be aware that anthocyanins are weak inhibitors of CYP3A4, which is required for the clearance of TKIs.
Anthocyanins and their metabolites are weak inhibitors of cytochrome P450 3A4
https://pubmed.ncbi.nlm.nih.gov/18727015/
Pharmacokinetics of asciminib in the presence of CYP3A or P‐gp inhibitors, CYP3A inducers, and acid‐reducing agents
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283742/
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The file is in PDF format and some links may not be working on clicks as they are broken to multiple lines, but copying the text into your browser should work. MS Word kept changing the formatting whenever I open it in a different browser, so I couldn’t use it.
Let me know if you have any problems accessing or reading the file. It’s in my personal OneDrive on Microsoft cloud storage.
Please share your thoughts and if you have any info and experience related to chronic inflammation.
https://1drv.ms/b/c/ac6792ec633b9974/EaAOHvR4tKlHmfM0-XkGTLYBjvrWLzpJ94w...
Zoran