Dr Silver, interferon and possible combos

[Paul123456]

See reference to NAC and statins near the bottom

journals.lww.com/hemasphere...

[JohnSC]

Good article. Thanks for posting.

[Manouche]

« We foresee a bright future for patients with an MPN, in whom early intervention with stem cell-targeted therapy, rIFNα, alone or in combination with drugs targeting the chronic inflammatory state, may allow many to achieve Minimal Residual Disease, thus becoming candidates for clinical trials employing vaccines leading to the possibility of cure »

[Manouche in reply to Manouche]

«… treating patients with rIFNα at the earliest disease stage possible, when inflammation is less pronounced, seems a more rational approach rather than a “watch and wait policy,” which permits the malignant clone to expand, thus increasing its inflammatory load.The early intervention with rIFNα has recently been supported by mathematical modeling studies. These show that the earlier rIFNα is started in PV and related neoplasms, the more rapid the decline in the JAK2V617F allele burden. This results in a shorter treatment period in order to obtain a major molecular remission. »

[EPguy]

Thanks much for the timely post. Much is familiar but it's well summarized.

Large studies, I interpret partly to be cumulative of the many small studies that have been done:

<<Many subsequent studies in more than a thousand patients have confirmed that rIFNα is safe and effective for treating essential thrombocythemia (ET), PV, and early-stage MF patients>>

But too many small ones:

<<Despite these impressive results, these were primarily based upon phase 2 or single-arm studies and did not satisfy regulatory requirements>>

Smoking is bad:

<<Smoking elicits a massive systemic inflammatory stimulus>>

Low tolerance to INF:

<<patients with myelofibrosis and massive splenomegaly, do not tolerate rIFNα well, owing to its side effects>>

can be addressed with anti-inflammatories

<<adding a potent anti-inflammatory drug (eg, ruxolitinib or prednisolone)>>

DNMT3A gene is important. My NexGen gene test included this one. But it can be lost during treatment if no CHR:

<<...demonstrated that genetic loss of DNMT3A conferred resistance to treatment with rIFNα>>

Older studies on hepatitis could be relevant. I have been seeing some of these incl an INF+NAC study.

<<Similarly, unresponsiveness to rIFNα-2a in hepatitis patients may be explained by oxidative stress, also impairing IFNα-2a signaling>>

INF+ Rux for refractory

<<our clinical trials in PV and MF patients who had been previously intolerant or refractory to rIFNα-2a monotherapy have shown this combination therapy to be both safe and effective>>

There are a lot of "may be's" in the report eg:

HU+ INF. Maybe try some HU before giving up on INF if INF isn't tolerated:

<<it may be rational to combine lower doses of HU with rIFNα, thereby reducing the increased thrombotic risk in PV and reducing rIFNα toxicity>>

I posted details on this a while ago:

<< Importantly, as previously discussed a recent study of 470 PV patients has shown that rIFNα yields improved myelofibrosis-free and overall survival,16 as does a recent meta-analysis>>

[Paul123456]

ETguy

You refer to Interferon toxicity. Are you able to expand on this?

My recent BMB showed increasing fibrosis (stage 1 to 2) despite 30 months of interferon. My inflammatory markers are very low (LDH c.100 when lower limit 130 and CRP under 0.3). Spleen appears fine but I have a scan tomorrow. Bloods all low, RBC c. 4.3, WBC c. 2, all suppressed by Pegasys despite having reduced dosage to only 30 mcg every two weeks.

My JAK2 was 80% pre Pegasys, dipped briefly below the magic 10% and now c.15%.

I’m awaiting results re fibrosis to see if any collagen, ie whether I’ve progressed to early stage MF.

I list the above because I show no signs of progression other than increasing fibrosis and appear to be responding well to Pegasys.

My Hem said let’s wait for the collagen and spleen results but if both okay, then maybe the Pegasys is causing the fibrosis.

I’ve not seen this before, just wondering if you have come across it.

I also have TET2 (was 50%, now 40%) which to some extent blocks Peg pathways with inflammation, bit like smoking. This might be a factor.

Thanks Paul

[EPguy in reply to Paul123456]

As Manouche says, INF is not known to be detrimental for fibrosis, Can your Dr provide a reference for this claimed possibility?

I've been looking into non-driver mutations. Did you also get checked for TP53, DNMT3A, and SF-- types?

I just posted:

healthunlocked.com/mpnvoice...

in which these mutations are of interest. They sometimes appear during INF therapy.

[Paul123456 in reply to EPguy]

Thanks yes I’ve had the full myeloid panel test for over 50 mutations. Only JAK2 and TET2

Re Pegasys possibly causing my fibrosis, it was from a top MNP Hem. I think I’m an unusual case

[EPguy in reply to Paul123456]

Did you get any full panels recently? According to these refs, some can emerge during treatment, and INF has a higher rate of such than HU. I will ask my Dr about it as my Besremi journey proceeds.

That idea of INF causing fibrosis progression, even rarely, is a big deal. It's not in any familiar publications. Can you ask your expert to add more details? This is of great interest to all of us since progression is a top reason for choosing INF. It is known that progression can occur while on INF but not widely known that it ever can be an accelerant for it.

[Paul123456 in reply to EPguy]

I think my version of PV is pretty unique so no need for others to worry about a read across. I will report back when I find out more. Getting spleen scan today

[gvibes in reply to Paul123456]

Hi Paul,I read the paper... maybe get an idea of where this might all be headed. Hunter has written about inflammation role in all this but its all been theoretical for me (I do take spoonful of fish oil every day) and never really talked about with doctor. I have PV JAK 2 but v617f negative, positive for exon 12 (the 3% mutation). I've been on pegasys for almost a year. Took some time to get going and seemed to be working in the fall. But then I had melanoma surgery with healing problems - ended up stopping pegasys at the request of the surgeon for 3 weeks. Started up again, with some of the same side effects that I had at the beginning of pegasys injections. eventually they subsided but its been a few months now and the pegasys doesnt seem to be controlling my hematocrit - went up to 50%. Phlebotomy and increased dose to 135 mcg/week. My point being, I noticed the reference to TET2 in the paper and realize that I have a TET2 mutation (5%) and started wondering if that explains some resistance I might be having to the pegasys. Certainly a talking point with my MPN doc.

Take care

[Paul123456 in reply to gvibes]

TET2 does impair the pathways used by Pegasys with inflammation. Smoking does the same. I pursue a fairly strict anti inflammatory diet and do plenty of exercise, hoping to keep my levels of inflammation as low as possible. There is an ongoing anti inflammatory trial at the moment so final results will be interesting, especially if can alter progression. Perhaps unsurprisingly, early results are positive re feeling better/reduced symptom burden.

[gvibes in reply to Paul123456]

what is that trial so I can read about it? thanks.

[EPguy in reply to Paul123456]

See also my recent post:

healthunlocked.com/mpnvoice...

TP53 and splicing factor mutations (SF--) are prognostic. but this did not study INF.

--

You're likely familiar with the RUXOPEG study. This follow-on included:

<<Most patients in the study were intolerant of or refractory to standard PEGIFNa2 treatment, and more than half had discontinued previous treatment>>

haematologica.org/article/v...?

It indicates improved results vs INF only for this cohort. Do you think this combo therapy could be worth asking about?

[Paul123456 in reply to EPguy]

Yes thank you. I think a Ruxo combo will be my last option. First option is switching to Besremi and I’m also now taking NAC 600 mg twice daily. I’m not on the trial but will wait for trial results with great interest.

I don’t read much about why interferons work better on some than other? We know that smoking and TET2 block the pathways used by interferons with inflammation but what about people with high levels of general inflammation (eg high CRP) through being overweight, poor diet, minimal exercise etc.

ie is general inflammation a problem or is it just specific pathways?

[EPguy in reply to Paul123456]

I've also resumed NAC. My Dr specifically ok'd it. Dr. Fleischman said not to delay my start of Bes to enter her trial. But I'm still on HU so can continue the comparison vs no-NAC. I will increase to 1200 next week. I get GI trouble when starting NAC (all 3 times) so best to take it slow.

Bes is supposed to be more consistent it its action because it has a single well controlled pegylation site. PEG has multiple and differing such sites. I've posted some thoughts on that before. There's also two flavors of the basic INF, alpha-a and alpha-b. PEG uses (-a), Bes (-b). (-b) is also in PegIntron. (-b) I think is more active in more areas of the body from what I can find. But it is also harder to tolerate, so Bes may have figured the way to solve that. I would not rely on this info, but it's my best guess from limited data I could find.

Hunter has posted well on the inflammation issue. I take it that it's a total body effect and I can say it feels like that (if I can separate from Long Covid) . It is a recent area of more study, Dr. Fleischman is focused here. So expect to learn more in the near future.

[Paul123456 in reply to EPguy]

Thanks for your reply. Re NAC trial, I know there are various cohorts but is the max dosage regime 1,200 mcg or 1,800 mcg daily? I’ve been on 600 mcg x 2 daily for the last couple of weeks. I’m doing my next bloods tomorrow including a JAK2 % so will be interesting to see if any changes.

I’m discussing the potential benefits of switching to Besremi with a couple of highly regarded Hems, in particular will it work better on a molecular level especially in view of my TET2 mutation. I’ll let you know their conclusions.

[EPguy in reply to Paul123456]

I think the max trial dose is 3600/day. From the info sheet for the trial

"All participants will receive 8 weeks of N-AC, participants will receive 1 of 3 dose levels (600mg twice daily, 1200mg twice daily, or 1800mg twice daily). "

For a small person like I am, 3600 would be quite a wallop since 600 seems to make a difference.

If you get a Jak2 response in a couple weeks of NAC that will be quite interesting. You may se it from just the INF. Let us know too about any symptom changes since starting NAC. Or is it restarting?

Interested also to hear any feedback from the top Hems on the NAC+INF you're taking.

As a minimum I'm expecting fewer symptomatic days.

[Pte82 in reply to Paul123456]

Paul123456, liposomal vitamin C may enhance the effect of vitamin C noted in this article.

pubmed.ncbi.nlm.nih.gov/288...

[Manouche]

Hi Paul, It seems that interferon has a protective effect against bone marrow fibrosis, not a fibrotic effect. Did you ask your haem whether your fibrosis could be due to the low dose of interferon ?

« interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response » pubmed.ncbi.nlm.nih.gov/262...

[Paul123456]

Agreed that’s what I was expecting. But it’s either not slowing progression, which is strange in view of my other markers, or it is somehow contributing to the increase to Grade 2, either directly or indirectly.

[Bluetop]

Thanks -the article summarises well. Interesting re statins. I am currently on Hydroxy and doing well, but my GP has suggested statins may be a good idea. No problem with cholesterol, but just for their anti inflammatory properties . I will discuss with haem

[gvibes]

Thanks for sharing timely paper.