JAK2 and TET2

[Paul123456]

Does anyone else here have this double mutation?

After nearly three years of Pegasys my JAK2 has dropped from over 80% to c. 14% but my TET2 has only dropped from 55% to 40%.

Got results of my recent BMB and no change in fibrosis, still ‘an increase in thin reticulin, especially in areas of focal clustering (grade 2/3)’.

Was hoping that my good molecular response to Pegasys, including LDH dropping from 250 to 105, might have improved my marrow but assume the lack of change is down to the TET2.

Be interested to hear if anyone else has had a similar experience

Also does anyone know whether collagen supplements are advisable or does this increase the risk of MF progression? My very limited understanding is that MF fibrosis is somehow related to the body producing excessive collagen?

dx 2016, JAK2, TET2, PV, MPN-U, Pegasys peaked at 120 mcg weekly, currently 30 mcg every two weeks since WBC over suppressed

[Manouche]

« With regard to the treatment, studies have shown that management with peginterferon alfa-2a can reduce JAK2V617F clones but not the TET2 mutant ones. As mentioned earlier, TET2 mutation leads to persistent clonal hematopoiesis [26]. Another study has shown that peginterferon alfa-2a-treated patients with both JAK2 and TET2 mutations had a less significant reduction in the burden of JAK2V617F compared to those with JAK2 but without TET2 mutations. The former group possessed a higher burden of JAK2V617F mutation at the beginning of the therapy. Furthermore, the same study revealed that patients without complete remission were more likely to have additional mutations apart from JAK2« cureus.com/articles/68356-j...

[Paul123456 in reply to Manouche]

Thanks so much, a very interesting article.

Best Paul

[Flynn2107 in reply to Manouche]

I have jak2 at 88% and Tet2 at 25% as of my BMB last March. I've been on 90 mcg Pegasys per week since mid August. My Dr will give me a genetic blood test at end of Jan 2022, I'll post my results when they arrive. Your results are impressive, jak2 is the driver mutation for p-vera, TET2 is a non-driver of less concern for p-vera, I think it has a tumor suppression aspect to it but not much has been studied with it.

[Paul123456 in reply to Flynn2107]

Hi Flynn

Thanks for your reply. Manouche’s link appears relevant to both of us re high JAK2 AB at dx. I think this does increase our risk profile, particularly in terms of new mutations. Hence good news if your doctor’s genetic blood test is the full myeloid panel?

Did your BMB indicate any fibrosis?

I think the problem with TET2 is that it’s inflammatory and blocks the pathways used by Pegasys. I’ve tried to compensate with a fairly strict anti inflammatory diet (with the exception of copious amounts of red wine) and plenty of exercise. My CRP is < 0.3.

Next consultation I will ask whether it’s possible to target the TET2, perhaps with Ruxo. Our Hems have tended to ignore TET2 as a potential therapeutic target but latest research appears to indicate that this may benefit the likes of us.

Also wondering whether NAC or metformin might be helpful.

[EPguy]

In this paper:

ncbi.nlm.nih.gov/pmc/articl...

<<RUX and AZA (Azacitidine ) demonstrated marked improvements in bone marrow fibrosis at 24 months when compared with RUX alone.>>

Could be worth asking your Dr. but this is for Rux combo rather than with INF.

On the TET mutation, nothing actionable here but interesting info:

This article studied the effect of the order in which each mutation was acquired. It can be determined after the fact according to this paper.

It seems to suggest Jak2 first has better response for both mutations with Rux, but as above no info on INF.

healio.com/news/hematology-...

<<In vitro analyses indicated Jakafi (ruxolitinib, Incyte) reduced single-mutant and double-mutant colonies in JAK2-first patients, whereas single-mutant and double-mutant colonies were unchanged in TET2-first patients.>>

[PhysAssist]

I did read somewhere else that having the TET2 mutation makes the MPN more resistant to INF-based tx, and that using a combination of a lower-dose interferon and Jakafi had better effect on molecular remission than higher doses of either alone.- AND less side-effects. Sorry, but i have been through so many articles and research reports that I can't remember where it was...