Non driving gene mutation-ASXL1

[merlisa]

I have MF with JAK2 V617F for 10 years, now is taking Ruxotinib and Interferon . Spleen contraction and blood control are good. Although I took a lot of hormones, at least my fibrosis degree has been reversed, and the mutation rate has also decreased a lot. But I was found I have a new bad prognosis gene mutation-ASXL1 with the rate of mutation is 15%~16%. What is the latest international approach to this mutation? I have no donor for stem cell transplantation, and I am extremely worried.

[Aneliv9]

Hello. This mutation is a new finding??? Is it a result/ effect from previous drugs (ruxolitinib and interferon)?

Also isn't it possible to find a donor on worldwide base?

[merlisa in reply to Aneliv9]

As I know, no drug for asxl1.

[EPguy]

Good to have such Jak2 reductions, and fibrosis reversal is great.

Did you have a test for ASXL1 before the recent new finding?

On ASXL1 latest info you ask about, some reports here. The nearest term agent may be Navitoclax combo with Rux, in trials, see last item.

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They are learning new details how ASXL1 works and with that they have a new idea to address it.

"...identified a first-in-class small molecule inhibitor that was able to inhibit BAP1 activity...they discovered that blocking BAP1 activity reduced the expression of genes upregulated due to ASXL1 mutations, ultimately suppressing tumor progression."

It seems for the 1st time there is a potential way to treat ASXL1. But it's still new research.

news.feinberg.northwestern....

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Here is a more specific report regarding ABT-737, a bit further along but still pre-clinical. ABT-737 has been known for some time:

"we provide preclinical evidence showing that the combination of ruxolitinib and ABT-737 is a promising therapeutic strategy for MPN patients with concurrent JAK2V617F and ASXL1 mutations"

researchgate.net/publicatio...

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Going further, ABT-737 seems to have evolved into orally available Navitoclax, which is in clinical trials in combo with Rux.

news.abbvie.com/news/press-...

[lakeview65 in reply to EPguy]

Thank you for this information, I will definitely read the studies. I have ET, Jak 2 is 9% alle burden and my Askl1 is 32% alle burden . I have been told that this is my driver mutation, not the Jak2. I talk to my MpN Dr and no one seems to know what this will mean for my future. Hopefully they will learn more in the future. I am on Hydroxyurea, for now. I have no side effects, maybe a bit of fatigue.

[EPguy in reply to lakeview65]

The Navitoclax study is recruiting for phase 3:

trial.autocruitment.com/mye...

[merlisa in reply to EPguy]

Thanks for your information. It seems to be a new drug, and now in clinical phase 3, it is still targeted at the JAK-STAT pathway, not the gene AXSL1.

[EPguy in reply to merlisa]

It is a confusing history. But if we coordinate the info here it leads to Navitoclax + Rux being of interest for Jak2 + ASXL1.

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ABT-737 + Rux is active against these combined mutations:

"In conclusion, we provide preclinical evidence showing that the combination of ruxolitinib and ABT-737 is a promising therapeutic strategy for MPN patients with concurrent JAK2V617F and ASXL1 mutations."

ABT-737 is identical in function to Navitoclax:

"Navitoclax, previously known as ABT-263, is an orally bioavailable analog of ABT-737 with identical function"

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However, you're right the Navitoclax trial is not directed to ASXL1, and so the trial is not following up on the connections above.

It could be they have found otherwise in their more recent experience, but the benefit seen is in a very fresh (Aug 2022) report. Maybe this result is so new that it cannot be added to the trial. But it should be knowable retrospectively at least as the trial proceeds.

If I had these mutations and qualified for the trial I would provide the info here and inquire in detail with the trial sponsors for their take on the ASXL1 implication, it does seem to lead that way.

[merlisa in reply to EPguy]

Hope ABT-263 could works on AXSL1. Your information is very valuable.

[merlisa in reply to lakeview65]

How many years have you known this result(AXSL1 :32% and JAK 2 9%) and kept it?

[SoledadBarcelona]

This is new or you have been it for years?

[lakeview65]

I have known this from when I was first diagnosed 18 months ago .