INTERFERON-ALPHA TREATMENT RESULTS IN THE DEPLETION OF DORMANT JAK2-MUTANT HSC IN A MURINE MODEL OF POLYCYTHEMIA VERA

[Manouche]

« The majority of patients with Bcr-Abl negative myeloproliferative neoplasms (MPN) have a JAK2-V617F mutation. Targeted therapy with JAK-inhibitors have been shown to normalize blood parameters but do not lead to a significant reduction in the mutant allelic burden. Interferon-alpha (IFNα) therapy is the only treatment option available that can achieve molecular remission. However, long-term treatment with IFNα is required and patients frequently exhibit adverse side-effects. Thus it is important to elucidate the mechanism of action of IFNα in achieving molecular remission, which is still not completely understood. Previous studies in JAK2-mutant MPN mouse model have shown that IFNα treatment leads to the depletion of the mutant hematopoietic stem cells (HSCs). Our previous findings have shown that IFNα can drive wildtype dormant HSCs into cell cycle, leading to attrition of functional HSCs. We hypothesize that IFNα treatment eliminates the functional disease-propagating JAK2-mutant HSCs by breaking their dormant status

. »

library.ehaweb.org/eha/2021...

[MPNBlog]

Thanks Manouche. Very interesting. If they can find out how Interferon reduces the allele burden, maybe other drugs can be used that have less side effects. It's interesting that Fedratinib doesn't affect allele burden - I thought it was considered one of the new wonder drugs. I'm having an allele burden test this week. I've been on Peg about 20 months with a 4 months stop at 15 months because of side effects. I'm wondering if I'm getting any effect on allele burden. Not everyone gets the effect. Knowing that would make it easier to cope with the side effects. I'm unsure how long you need to be on Pegasys to have an effect. But this test (on mice) was only 4 weeks and it had an effect.

The Interferon Project was going to look into all that. I haven't seen their findings and I think that project has recently would up. Do you know what they found? Thanks.

[Manouche in reply to MPNBlog]

An effect on the allele burden usually takes about 2 years of Interferon treatment. A total eradication of jak2 mutation can take 12 years or more.

« Interferon alpha (IFNα) treatment induces not only a hematological response in around 70% of ET, PV and early myelofibrosis, but also a significant molecular response on both JAK2V617F- and CALR-mutated (CALRm) cells. However, a complete molecular response is only achieved in around 20% of patients. »

library.ehaweb.org/eha/2020... un

[MPNBlog in reply to Manouche]

Thanks Manouche. Very interesting. There's still a lot to understand and a lot more research is needed. It seems that high doses of PEG are best to reduce allele burden, but unfortunately I can't tolerate more than 45 ug. It also seems that homozygous JAK2 is more likely to respond. I haven't heard discussion about that on here. Do you know how you can find out if you have homozygous or heterozygous JAK2V617F? Thanks.

[Manouche in reply to MPNBlog]

I never had the heterozygous/homozygous test done and my

haematologist doesn’t seem to be interested. The jak2 allele burden test is more than enough for most of the hematologists.

[MPNBlog in reply to Manouche]

Thanks for getting back, Manouche. Best wishes

[Bluetop]

Thanks for this really interesting article. I am PV JAK 2 positive and have been on hydroxy for 5 years now -without problems, but nevertheless I really don't understand my haems reluctance to switch me to interferon -(despite potential side effects).

[Flynn2107 in reply to Bluetop]

There was a study on humans that showed reduction in the jak2 mutation. Attached is a press release with the basic findings of the Proud-PV study. The ropeginterferon is called Besremi in the EU where it has been approved for use in ET and PV patients. The US FDA is expected to approve the drug this year. This interferon has a sugar molecule added to it that gives it a slower release in the body and fewer side effects. For the in-depth research results do a search on the Proud-PV study and its follow on study called Continuation-PV study. businesswire.com.

[Flynn2107 in reply to Flynn2107]

Here is a better link to the story. ema.europa.eu/en/medicines/...

[Bluetop in reply to Flynn2107]

Thanks for these. My understanding is that Besremi is not yet available in the UK, but that I could switch to Pegasys. I think my haem is questioning that whilst there is evidence of molecular response with interferon, there is not a heap of evidence to show the advantage of this.

[Manouche in reply to Bluetop]

Some haems find it more time consuming to have patients on Pegasys as it can take months to find the right dosage. I suppose that’s why many prefer to have their patients on HU.

[Bluetop in reply to Manouche]

Yes, I think there is an element of 'if it 'ain't broken don't fix it'.

[Flynn2107]

Here is another link. businesswire.com/news/home/...

[Bigcheat]

Thanks Manouche.

I have booked a meeting with my hematologist to discuss the possibility and risk/reward of Pegasys. I was diagnosed with ET JAK2 last year and been on aspirin only therapy since. Platelets have been climbing around 25 units per year for past 7 years or so, being now at 530. In my country Pegasys is reserved for high risk only, but my doctor said I could buy for it myself.

My symptoms are quite manageable but I have this belief that treating early would give better odds for a good molecular response. I have some history of anxiety which could worsen due to Pegasys which is of course adding to the risk side of the equation. If anyone can relate to this, please comment. I would like to know how others are reasoning with starting or not starting with Pegasys while being in low risk group?

Cheers,

Bigcheat

[Manouche in reply to Bigcheat]

In my opinion, the wait and watch approach is totally outdated. Cancers always get worse with no treatment. You’re doing exactly the right thing, i.e hitting jak2 as early and as hard as possible.

[JaK2ET in reply to Bigcheat]

I was diagnosed with JaK2 ET in Feb 2019 (aged almost 60) and for nearly a year I was on low-dose Aspirin (plus supporting medication for GI tract protection some of the time - another story in itself). Early in 2020 cytoreductive chemotherapy with Hydroxycarbamide (Hydroxyurea) was added to my treatment and over the next year or so I saw a gradual fall in my platelet count (bringing it into the normal range) and some improvements in my physical and mental health.

Unfortunately a leg wound developed about a year ago which (unlike two somewhat similar wounds in 2019 that eventually healed by themselves) does not seem able to heal; I suspect that the chemotherapy is making this healing more difficult or perhaps impossible. My haematologist now wants me to switch to Interferon, probably PEGinterferon, and this is causing me some anxiety. The reasons are: 1) the medication has to be injected; 2) there is a long list of common side-effects, including mental health effects. Although my only formal mental health diagnosis is mild OCD I don't have great mental health (and one of my siblings has serious mental health problems). To counteract these negative feelings, I am trying to remind myself of all the papers etc I have read online by leading experts in MPNs who favour Interferon as the only treatment (apart from stem-cell transplantation?) that has any chance of actually "curing" the underlying disease process, rather than just managing the symptoms ...

Good luck with your decisions and treatment!

[Bigcheat in reply to JaK2ET]

Hi Jak2ET,

Thanks for sharing your thoughts. Mental health problems are part of my family history, so it puzzles me. But also the physical side effects, and potential elevation of liver enzymes, which are already high to begin with. I wonder, if side effects were to emerge, would they alleviate as soon as injections are stopped? Or would they fade slowly over weeks or months?

Cheers,

Bigcheat

[JaK2ET in reply to Bigcheat]

It might be worth you starting a new thread on side-effects of the latest/most modern types of Interferon/PEGinterferon, so as to tap into the experience of other members of the forum who have used them, discontinued them, etc ...

(Looking at some cancer-related websites, I was alarmed to read that 20 - 30% of patients who try Interferon tend to discontinue the treatment because of the side-effects. My haematologist suggested that the PEGinterferon causes fewer problems than the older kinds.)

[Bobadog]

Hi Manouche,Many thanks .I have my telephone consultation with Prof Harrison tomorrow.

This information will greatly help me enquire into further tests for my current allele burden,and potentially different treatment.

Previous test (2015)

Unfortunately I am not improving on repeated venesections

Thanks