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ASXL1 Mutation

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Hello,

How many out there have this mutation?

For those who have or had it, I have several questions.

1) How have you and your team addressed this in general?

2) Did you experience TKI resistance?

3) Have you and your team looked into ALOX5 inhibitors?

For #2 and #3, I've come across some interesting studies. One of the more interesting studies is:

CML With Mutant ASXL1 Showed Decreased Sensitivity to TKI Treatment via Upregulation of the ALOX5-BLTR Signaling Pathway

PMID: 39905783 PMCID: PMC11967257 DOI: 10.1111/cas.70007

Thank you and look forward to your input.

Hi there,

I‘m sorry I haven’t seen your post earlier.

I have it, G646T on ASXL1 and also F317L on ABL1. I‘ve been taking Asciminib and Dasatinib, first half a dose till peripheral blood stabilised, now full dose.

F317L is resistant to Imatinib and Dasatinib. While on Nilotinib, Bosutinib and Asciminib, my peripheral blood was okay, but BCR fluctuated between 10 and 40. After a while I was informed that I have G646T and was recommended Ponatinib or BMT, but I refused both. Then I tried the combo option and it worked, but was too strong, so had to stop and resume half a dose, which normalised blood counts, but had no deep effects on BCR.

Now on full dose I hope to see deeper response. I feel well, there are no issues.

I found 2 ALOX5 inhibitors, Zileuton and Montelukast, however Zileuton is not available in Europe and Montelukast seems a bit dangerous.

https://share.google/aimode/XiROnK54wS1uOkd6j

https://share.google/aimode/KYxMgrP6wLFEUprdC

https://ashpublications.org/blood/article/126/23/4835/93445/Alox-5-As-a-...

https://onlinelibrary.wiley.com/doi/10.1002/jcp.30301

https://pubmed.ncbi.nlm.nih.gov/19503090/

I‘ve been taking natural leukotriene inhibitors which improves overall wellbeing and energy, it also fixed a nasty rash I had on my head - some kind of follicle inflammation caused by the combo therapy.

I gained 14 kilos since September and I think it's also somehow related to inflammation.

I shared some documentation with my doctor and will ask him how to get Zileuton. I think it could really help with both resistance and LSCs.

Hello and thank you for your detailed response.

I recall mentioning Zileuton to my CML specialist. He was unenthusiastic about any ALOX5 inhibitors. He stated they are not worth the trouble.

There is still a part of me that wonders ALOX5 inhibitors have a place for ASXL1.

I have been taking Boswellia, a herbal supplement, as I've come across some interesting studies which indicate it may work in inhibition of ALOX5. I don't know if it is working but there are no contraindications in my case.

Another ALOX5 inhibitor appears to be caffeic acid but I haven't tried it.

I will bring up Zileuton again when I meet with the specialist later this month.

Re: the natural leukotriene inhibitor, last year I found a study which mentions this but did not think much of it. Your post has made me very curious on exploring this! Thank you!

https://onlinelibrary.wiley.com/doi/10.1111/cas.70007

"ALOX5 downstream signal inhibition by LY293111, a leukotriene B4 receptor (BLTR) antagonist, suppressed AKT phosphorylation and enhanced TKI sensitivity."

FYI: There are currently three new TKIs in development which appear quite promising. I don't know what the status is in Europe as I'm in U.S.

Olverembatinib
This has been in use for over 5+ years in China with impressive results. I know it addresses T315I with less toxicity of Ponatinib. It is scheduled to be released later this year in U.S. (based on what an oncology nurse and fellow CMLer told me).

ELVN
This is still in the testing phase. But the early results are very impressive for CMLers who did not respond to multiple TKIs (including Asciminib). It is ATP competitive, if memory serves me.

TERN
This is still in the testing phase. Again, very impressive preliminary results. This binds to the myristoyl pocket. In other words, this has the potential to be a better version of Asciminib. The way I see it, why would anyone go through the trouble and expense of developing a myristoyl pocket binding TKI if it's just going to be as good as Asciminib?

These drugs, if/when approved, may be the next evolution in CML treatment. For those who can tolerate an ATP competitive+myristoyl pocket binding TKI, I strongly suspect this can be an improvement over current drugs in use.

Thanks again and please feel free to update on this subject. I'm very curious on how things go should you try Zileuton.

EDIT: I believe I have been consuming caffeic acid all this time - in the form of coffee. I would still like to add other compounds such as Zileuton, if possible.

Hello,

If you are in the US you may want to try AKBA which is a more potent version of boswellia. It's available from Pure Encapsulations.
I also take betulin, curcumin, vitamins e and d.
Quercetin is another powerful ALOX5 inhibitor, but it causes me chest pain so I avoid it. I ordered rutin, which is a less potent cousin of quercetin, but haven't tried it yet.
I've also ordered baicalein which is a potent ALOX15 inhibitor, but haven't started taking it yet. It also inhibits CYP3A4, so should be careful.

https://share.google/aimode/iT9GgOm3Gyi53g1Wb
https://share.google/aimode/QwjuBK3w4tJ91Eaw4

It's important to spread these throughout the day, e.g. take some every 2 hours, just as they recommend it for Zileuton, but at least 2-3 hours away from TKIs.

What TKI you take and how it's affecting your BCR?

New TKIs are great for newly diagnosed, but waiting for these is probably not wise for people with ASXL1 mutations.

I've tried mebendasole, which is cytotoxic against CML even at nano concentrations and does not discriminate against LSCs. However, it's an allosteric inhibitor which attaches to ABL1, just like asciminib, but it's slow acting like interferon, so it seems it competes with asciminib, unlike thought by the researchers, and caused my platelets to go up, so had to stop it. It should synergise with ATP competitive TKIs and should be taken for at least 6 months just like interferon. I took it for 2 months, confirmed twice it's increasing platelets count, but didn't cause any side effects.

There are ways to enhance TKI absorption which translates into higher exposure and deeper response. I added vitamin c and k2 to TKIs.

Exposure > effects:
https://pubmed.ncbi.nlm.nih.gov/18256322/
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar...
https://pmc.ncbi.nlm.nih.gov/articles/PMC12109594/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4950523/

Enhancers:
https://journals.sagepub.com/doi/abs/10.1177/1078155217692152
https://www.mdpi.com/1424-8247/16/11/1527
https://pubmed.ncbi.nlm.nih.gov/35778632/
https://pmc.ncbi.nlm.nih.gov/articles/PMC10478393/

At the moment I take half a dose TKIs twice a day as both have very short half life (plasma concentration drops below 50% within 4-5 hours). Once BCR stabilises, I will switch to full dose once a day as plasma concentration increases more than double and leads to deeper response. For example, asciminib 40mg peaks at 800 ng/ml, while 80mg peaks at 1800 ng/ml. They say that higher even short-lived transient peak makes deeper impact.

https://share.google/aimode/bp0ZTB4sReds9Bl44

I also drink coffee, but mostly espresso from Arabica, while AI suggests it is Robusta that inhibits ALOX5. I guess I need to adjust there as well. :)

https://share.google/aimode/J8bTWRem9qYbDzSwo

Thanks very much for the info!

For some reason, my user account switches between 56x11 and StayStrong3916. I must've have created two separate accounts.

Currently on scemblix 20mg. The dose I take is small because any and all TKIs drop my platelet count.

BCR fluctuates and I was warned about not panicking by several specialists. Currently using basophils as a proxy while still testing BCR every three months.

I believe you're on the right track using ATP and myristoyl TKIs. I, unfortunately, do not have that luxury.

Will look into AKBA.

I had no idea re Robusta. Will look into it.

baicalein is something I'll have to avoid. Although I've been tested as a normal metabolizer of CYP3A4, I need to avoid any inhibitors or inducers.

Fascinating how mebendasole may compete with scemblix. Will need to avoid that as well.

I also take D3+K2. I add magnesium glycinate for overall health and I've read it helps with D3 absorption. Where I live there is plenty of sun; therefore, I try to get about 15 minutes exposure in the morning for natural D as well as natural infra red light.

I've tried artificial infra red light and noticed it increases ALL my counts. The platelet increase is welcome. Unfortunately, basophils (absolute and percentage) also increases. Therefore, I stopped artificial IR.

There is a youtube vid with an Infra Red Light specialist out of University College London. I don't recall his name but he did warn against artificial IR for cancer patients. This video is several years old at this stage so I don't know if he has changed his stance.

Because I have no formal scientific training, it'll take several reads of the studies you provided for me to get a good handle on them.

Thanks again and let's stay in touch!