INF, allele and more

[EPguy]

I posted this in a reply thread. Seems of possible general interest.

In my opinion based on these and other info I've read, INF does more than just cut allele, there are weakly understood complex effects that are of separate benefit. But allele reduction could be a proxy for these benefits (I have no explicit info stating this)

Some clear results should come in the far future with MITHRIDATE for which our favorite forum is a collaborator.

clinicaltrials.gov/ct2/show...

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This prospective study is old by standards of MPN (2010) and things are not that simple anymore. But I've not seen this one before. Their claim is a current allele is correlated but not whether reducing it will help, as it predates most studies that looked at allele reduction.

nature.com/articles/leu2010148

<<We state that mutant allele burden is a risk factor for disease progression into post-PV MF...The risk of developing AML was not significantly related to the mutant allele burden>>

<<Studies in PV patients will clarify whether a reduction of the allele burden by treatment may prevent evolution into MF.>>

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More recently we keep seeing this statement:

mdpi.com/2073-4409/10/12/35...

<<IFNa has regained interest as a potential tool to interfere with the disease course>>

But there is this conflicting statement (I suspect from a different of the authors):

<<To date, therapeutic options are capable of reducing symptom burden (and partially even induce molecular remission), but not of effectively modulating the disease course in the majority of patients.>>

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Another study

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

<<A rise in allele burden has been correlated with progression to myelofibrosis in mouse models [33] and is consistent with observations of higher allele burden in MF patients compared to PV and ET>> Suggests stopping the rise is a good thing.

<<homozygous mutations are associated with a greater risk of progression to myelofibrosis>>---I don't know whether I have homozy or heterozy but the former responds better to INF based on recent info from ContiPV. If you have known homozy it is a further reason to consider INF.

<< Treatment with IFNα stimulates both JAK2V617F-positive and WT quiescent stem cells into cycle but leads to a preferential depletion of JAK2V617F LT-HSCs in mice and inability to develop MPN with serial transplantation with JAK2V617F mutant cells subsequent to IFNα treatment>>

-----This is new info to me. Putting bad cells in an INF treated mouse does not lead to mouse MPN. I've seen this for an experimental ATO-INF therapy, but not INF alone. This suggests INF causes something more than simply allele reduction.

Regarding MF INF gives <<a strong correlation between overall survival and longer duration of IFNα therapy >> This is unusually definitive for one of the MPNs.

<<Concomitant TET2 or DNMT3A mutations are associated with molecular resistance to interferon>> So if you have these, INF may be less effective, although Hunter is doing well on PEG with TET.

This study also has many details on non-driver mutations.

[jointpain]

Thank you ETguy. You are a wonder😁 each of us that, have, or in my case care for my wife who has a MPN must be in awe over your dedication to getting information about this disease.

[EPguy in reply to jointpain]

Thanks for the kind words. I enjoy learning for our collective benefit.

[Bluetop]

Thanks very much for all this information. A switch to Peg. is something I am seriously considering, even though Hydroxy is keeping my numbers managed with no phlebotomies and I have no symptoms. On the one hand its a case of 'don't fix it if it ain't broken', on the other hand the potential for remission is very appealing, plus the less toxic side effects. I am thinking of waiting for Besremi to become available in UK.

[EPguy in reply to Bluetop]

I'm near where you are, but I do have on and off symptoms. HU is doing its thing fine, but its thing is not a great end game to me.

[Meatloaf9]

Hi ETguy, the last paragraph in your post says that DNMT3A mutations and TET are associated with molecular resistance and that interferons may be less effective. I have the DNMT3A mutation. The last MPN research foundation newsletter said that the MPN interferon initiative considered DNMT3A a secondary mutation that leads to INF resistance but - preclinical work did not show that anticipated result- When I asked my MPN specialist about DNMT3A he basically said that the jury was still out on the significance of it. I have PV and have been on HU for 6 months and so far counts are WNL. When I asked about switching to Besremi, his advice was "If it ain't broke don't try to fix it". Since HU and INF seem to give about the same results for the first 2 years I am going to wait awhile to see how others do on Besremi before trying to access it. It will depend a lot on what the copay for a 180K per year drug is going to be, at least for me with a medicare part D drug plan.Thanks for all the research and sharing of same that you do for the MPH community. Best always.

[EPguy in reply to Meatloaf9]

You're right about uncertainty on mutations, even the driver ones are still revealing new info regularly. This paper listed others:

<<Concomitant TET2 or DNMT3A mutations are associated with molecular resistance to interferon [200]. The FIM study also showed inferior response to IFNα in patients with high molecular risk (HMR) mutations (defined as ASXL1, SRSF2, EZH2 and IDH1/2)>>

The FIM study here stated <<Mutations in any of these genes (the last four above) dramatically decreased overall and event-free survival of the affected patients and the presence of more than one additional mutation conferred an even worse outcome.6,7>>

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

Implication is these are worse than TET2 or DNM3A but no info on INF resistance for them.

This FIM study is interesting, I will check it out further and comment if it's worth doing.

The INF experts say starting early is preferable. At that 2 year mark INF should be well on its allele reduction curve while any equivalent HU curve is spent. (according to the ContiPV plots I've posted) I plan to switch if, as you say, it is affordable.

[Meatloaf9 in reply to EPguy]

Thanks again for posting this information, I am sure it takes a lot of time and research to find this info. Glad you are on this site. Please keep up the great work. Please let us know how you fare in accessing Besremi.

[Elizka]

How thoughtful for you to recap all this reverent research! IM0, this community is lucky to have you as a member.

[Elizka]

My hematologist is part a University hospital and was a fellow with a well-know MPN expert. He has told me the jury is still out on impact of mutations in MPNs.

[EPguy in reply to Elizka]

He's right about that. My searching has a bias to look for just such info and form my opinions.

Currently there are two ways we've seen to reduce allele, Jaki (eg Rux) or INF. So far I've come across more (but limited) data on implications of INF against progression and for survival. There may be plenty for Rux but most seems focused elsewhere. The best PV trial I know for Rux is the RESPONSE studies, and this symptom + blood control is tempting. But also the vax trade off I've discussed elsewhere is a downer.

news.cancerconnect.com/myel...

<<Because there is no cure for PV, symptom control is critical for the health and well-being of patients>>

If there are data on progression/survival for this study, it would be great info, it seems long term enough to gather such data. Some INF guys are considering these deeper goals as I've been searching.

Still Rux seems an excellent therapy for the right patients.

Interesting note in a related interview with our familiar experts:

onclive.com/view/polycythem...

<<ruxolitinib in myelofibrosis, which was the first indication, was associated with anemia and thrombocytopenia as an adverse effect. These are benefits in PV. >>

But it still feels blind on the very long term questions.

[Elizka in reply to EPguy]

Another great post!

For me, I didn't see any advantage for Rux. I don't have symptoms that impact my life and without the possibility of stopping progression I didn't see the benefit.

[Elizka in reply to EPguy]

I keep hoping that one day the medical world will figure out how to kill/turn off the Jak2 mutation. We weren't born with it, we acquired it, now how can it be deleted? Gene therapy? Anyway, this is what I hope happens.

[EPguy in reply to Elizka]

So far it can only get turned down, but by a lot sometimes. There is a very preclinical combo I've written about ATO-INF that essentially eliminates it in mice. But it's a long way from our grasp. 1st it needs a better ATO, my Dr reacted quite scared to the current IV ATO which is not easily used.

The better ATO: ir.syros.com/press-releases...

I've recently had the very simplified thought that there are three main ways the allele gets treated based on my understanding of these agents:

HU- suppress Jak2 successors

Rux - Suppress/delete Jak 2 directly

INF-Suppress/delete Jak 2 precursors (apparently along with other less studied malevolent agents).

Would be curious if extra simplified take is accurate.

[EleanorPV]

When I got my JAK2 test(2016) it didn’t come back with a quantitative figure. I hope this research will encourage the JAK2 results to give a % AB, throughput the UK.

[EPguy in reply to EleanorPV]

At least some UK members here have reported allele % results. For some maybe the Drs have it but don't share. Anyway you're right, this number is important esp for future reference.