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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.