How IFN targets Jak2 mutation

[EPguy]

A fairly recent report discusses how IFN works against the mutation. I posted in a thread, but seems worth a top post. It's complex stuff but seems consistent.

-In sum, it seems IFN forces damage to otherwise hidden Jak2's by stirring things up, but mutant ones fail faster once stirred.

--

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

Normal marrow stem cells (HSC) stay quiet, unless and until something requires action like infection or chronic blood loss. Then they wake and produce blood cells or more stem cells. It seems mutant ones also stay relatively quiet at least in this context.

In several reports, IFN causes HSC to exit this quiet (quiescence) state and become active without those natural causes. Both normal (wild type, WT) and mutated Jak2 (v617f) are stimulated this way. But the v617f ones wake up more and get more DNA damage once they wake up and thus die out faster than WT cells. So we need to lose both good and bad Jak2's to be rid of the bad:

"peg-IFN-α treated Jak2+/VF LT-HSCs (mutant Jak2s) showed greater reduction in quiescence and greater accumulation in G1 phase (a growth stage in cells, G0 is no action) , higher ROS (oxidation stress) production and more DNA damage compared with peg-IFN-α treated WT LT-HSCs"

So the good jak2s also activate but the bad ones go nuts and wear out.

Implication is if one has a mutant burden of 100% this process won't work since there are no WT Jak2s to waken. But this is not addressed.

In this report immune response is not a focus, no doubt this is involved in these processes.

This report also has a good quality comparison of Rux and IFN for allele reduction with the note "(Rux) patients with JAK2V617F show only minor reductions in mutant allelic burden, even after long-term treatment, suggesting that ruxolitinib is unable to eradicate MPN disease-initiating cells." I've seen this in other reports, Rux can reduce allele but not as often nor as much on average. Their intent is to contrast this result with IFN. But the effect on spleen was quite good.

--

They cited this one, which supports that forcing HSCs to wake up damages all HSC types, this is in context of getting old normally:

"Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs"

pubmed.ncbi.nlm.nih.gov/257...

--

Other reports suggest the old non-Peg IFN stirred things up too often and the HSCs eventually stopped waking up, but PEG IFN gives enough time between doses for recovery and fresh HSC waking. This could support longer dose intervals if we have the option.

[FG251]

I wonder how/if it’s possible to detect minimal residual disease after IFN use, from a clinical/haematological standpoint, without undergoing any molecular testing? In other words, could one assume a ‘steady state’ or ‘remission’ simply by the stability in one’s platelet numbers over the course of time? If the ratio of WT to mutated cells reaches an optimal number, presumably one’s counts don’t continue to be exhausted, but plateau?

[EPguy in reply to FG251]

In some of the reports that had stopped IFN treatments, they monitored blood counts. As you say, if counts hold steady it implies remission. In this report

"Remarkably, 7 patients (28%, 4 essential thrombocythemia, 3 polycythemia vera) have sustained their HR after discontinuation of PEG-IFN-α-2a (median time on therapy, 77 months [IWR, 56–98 months]; median response duration off study, 6 months [IQR, 4–34 months])."

So at least one held HR for 3 years absent IFN.

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

But this same report shows that complete MR is the most effective result for having CHR.

On the ratio of WT/allele, the report has: "presence of the JAK2V617F allele at very low levels in more sensitive assays (level of detectability, 0.1%) 11,25,26 in patients who achieved a CMR with PEG-IFN-α"

But in the Ropeg study they went as low as 0.014%. Here is a plot I created from the ContiPV data that shows the lowest allele % achieved in relation to CHR. So very near zero is possible, and might keep going down as detection get better. And CHR is related to MR.

So an older study used 0.1% and a newer one used 0.014 as detection limits.

CHR vs AlleleRopeg

[FG251 in reply to EPguy]

Thank you!

I suppose the burning question is, what level of MR (if one doesn’t achieve a CMR) is necessary for delaying/preventing disease progression. Any thoughts?

[EPguy in reply to FG251]

As I read all the reports we see they become hard to separate, but with enough repetition they also become familiar.

With that in mind, my feeling is the there is a disproportionate benefit to being close to the MR detection limit. The term CMR is used loosely, sometimes providing for well over this limit.

In the ContiPV for example at <0.014% was only 5.4% of patients, while .01-1% was 14%. So the very best results were achieved by only 5%. With that, less allele in general is better, I will be glad to have that.

But as always, among averages, most, whether low or high allele, will not progress.

[FG251 in reply to EPguy]

Thanks, again! Hopefully this will all be academic if the drugs currently being researched and trialled can improve on IFN still further.

[EPguy in reply to FG251]

I'm not aware of any breakthrough fixes en route to us. Any info is welcome of course. One exception is potential immune therapies for CALR.

But I do think we'll see IFN combos that provide big steps for us. I've posted some long ago, but none are in trials to my knowledge.

Notably when IFN was used for Hep C it was always with a 2nd agent. (Ribavirin )

[Manouche in reply to EPguy]

 »In the ContiPV for example at <0.014% was only 5.4% of patients, while .01-1% was 14%. So the very best results were achieved by only 5%. »

5% of patients got their best results after 5-7 years, but some data show that molecular response keep improving over the time even though lower dose might lead to lower or slower response.

[EPguy in reply to Manouche]

I've been looking for data after 5 years. Conti PV was quite selective what they showed for year 6, the basic allele plot stops at year 5. In this report, discussed before, only the best responders had sustained results after year 5.

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

Are you aware of some other data after 5 years?

7 year IFN

[Hopetohelp]

interesting read and thanks for simplifying

[Exeter21]

thnx for this good information . Julia UJ 👍

[Manouche]

No statistics but this: « The JAK2V617F mutant allele burden continued to decrease with no clear evidence for a plateau »

ascopubs.org/doi/10.1200/JC...

[EPguy in reply to Manouche]

This one seems to go to 2 years:

"Long-term follow-up of this cohort of patients will assess whether this trend is maintained beyond the 2-year landmark."

I'm curious, and maybe suspicious, why ContiPV has not published the 6 year plot. This is the only other long term study I know of that has such data.

But this part of the report you have here is consistent:

" None of the patients in whom the mutation became undetectable had a molecular relapse."

So the goal for IFN is to know why only some achieve that zero flat line in the plot above.

The report is consistent also that by 2 years, one will know whether CMR is likely, plot from the report here, Fig D. I think PV-1 is actually a typo, they mean the 2nd ET patient

The report used a allele sensitivity of 5%, which likely reflects its 2009 vintage. So complete MR could allow for 5% if I understand.

Interesting nugget on homozy vs heterozy:

"...were considered homozygous for the JAK2V617F mutation because they carried more than 50% mutant alleles." So if you are over 50% you are for certain with homozygous Jak2 allele.

CMR ET-PV

[Manouche in reply to EPguy]

« So the goal for IFN is to know why only some achieve that zero flat line in the plot above ».

Different IFN posology, different non-driver mutations, different age, different medical history, etc…I suppose many factors can explain the different level of response to the treatment.

[EPguy in reply to Manouche]

From all I've read, the only consistent correlation is to CHR. But CHR does not assure CMR. All the reports that have discussed it have said dose and MR are not related, this has also been consistent. I've looked to this extensively because my Dr keeps wanting more dose. But there's always room for more data.

On non-drivers, there are associations. From the FIM study in this post:

healthunlocked.com/mpnvoice...

"Concomitant TET2 or DNMT3A mutations are associated with molecular resistance to interferon" By molecular I assume this is separate from HR. 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)"

But absent those non-drivers does not at all assure CMR, which seems to range from ~5-20% of patients depending how's it's defined. So there still needs to find that magic potion to add to IFN that overwhelms all these vague complications and makes it crush the allele for more of us.

[Manouche in reply to EPguy]

 »All the reports that have discussed it have said dose and MR are not related »

Molecular Response is not dose related , but Complete Molecular Response/remission appears to be correlated with higher dose of weekly peginterferon.

[EPguy in reply to Manouche]

That is most useful info. Do you have some reports we can see?

This could explain why my Dr wants to keep upping it, but I found only the non-correlation reports.

I have seen one that posits that heterozy Jak2 needs more dose than homozy, but I followed their citations and could not find it.

[EPguy in reply to Manouche]

More on the report here:

They found in general that IFN did not improve allele for ET, see chart.

"Whereas patients with PV experienced a marked decrease of the mutant allele burden from a median of 64% before start of PEG-IFN-α-2a therapy to 12% after 24 months (P = .0009), this decrement was not significant in patients with ET."

But: "However, one should also note that our patients with ET seemed to have more aggressive disease than usual, with many patients carrying cytogenetic abnormalities"

We await the results of Ropeg ET trial.

PV vs ET allele resp IFN