A report on MF

[EPguy]

This is a short discussion of MF.

Some selected items:

It's about inflammation, as we know. One of the key players in this is interleukin-1 beta (IL-1β), which seems a particular finding of his group. "His research suggests that IL-1B’s influence is especially felt in the beginning of the progression towards MF." No direct mention of acting on this specific finding but an anti IL-1β therapy might be a direction from his early work

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Marrow damage level:

"there has to be critical threshold damage of the microenvironment to really lead into disease manifestation" This level or time to reach it varies among pts.

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The importance of fibrosis in MF rather than just the clone:

"If the ecosystem of the bone marrow is too damaged, no treatment aimed solely at the malignant cells will be enough."

Meaning just reducing Jak2 allele for example won't by itself remedy the MF condition. We've had posts on how important fibrosis level is, or isn't, usually in context of ET or PV. Here Dr Simón Méndez-Ferrer is focused on the importance of fibrosis for MF. This might fit to the damage level item above, fibrosis doesn't make trouble in ET or PV but if various conditions reach a certain level fibrosis becomes important.

mpnresearchfoundation.org/n...

[JP1952]

Thank you for that synopsis, something I could understand and found interesting. My haematologist never talks about inflammation or any disease management apart from medication. However, I strongly believe my symptoms are driven by inflammation .

[EPguy in reply to JP1952]

MPNs are inherently about inflammation. Many other conditions are also esp some other cancers, so it's a broad area to cover. I think it requires a holistic sort of Dr to appreciate, these Drs are rare.

[msr6637]

Curcumin (turmeric) and ginger lower IL-1B

[EPguy in reply to msr6637]

I found those various reports. Curcumin has other benefits too so with Dr being informed it could be worth a try. It could be best if one can get a IL-1β blood test for reference, but I think this test is not a standard in clinic so likely requires self pay and a cooperative Dr. I will ask my Dr next appt in July. But I'm not currently at risk for MF so it would be an early baseline in my case, but my guess is early baseline is where it is most useful.

Curcumin can be hepatoxic in the high dose forms currently popular so watching the CMPs is important.

[JP1952 in reply to EPguy]

Sorry, what are CMPs?In my early days of diagnosis and plagued by the dreaded itch I became a big fan of Angela Fleischman's talks. I took curcumin supplements which I bought from the chemist and I believe they helped, but I wasn't allowed any supplements when I did the Mithridates trial. Incidentally my haematologist didn't know what curcumin was. My participation in that trial has now finished and I had my 3rd BMB at the end, unfortunately it was suboptimal and the haematologist doesn't want me to have another one, apparently the bone just disintegrated when extracted. So I don't know if I am progressing towards MF but it was mentioned at my last appointment. I continue to take 20 mg Rux every day but all my bloods are below normal range except platelets which are 500+ and rise a little every test. Am a bit nervous of taking anything unless prescribed or recommended by a trusted source.

However many thanks for your input.

[EPguy in reply to JP1952]

CMP is complete metabolic panel. This report has its components. Of common interest in MPNs is the liver and kidney results. Some of our therapies can affect these organs, so the Dr should be doing these tests. Interferon for example often impacts the liver and might lead to dose adjustments or discontinuation in certain cases. Rux and HC also also might have liver effects, although we don't see that as frequently here. The other standard blood test is CBC(FBC) which is for more direct MPN effects rather than effects of the medicines, including platelets, HCT white blood cells etc.

my.clevelandclinic.org/heal...

Do you know which treatment you got in the Mithridates trial?

Agree on the risks of some supplements, some require close attention to use safely.

If Rux does not work out for you there are several newly approved medicines in the same class that your Dr may discuss.

[JP1952 in reply to EPguy]

Thank you for your reply. I am in the UK and think it may be difficult to get a CMP as part of my treatment on the NHS. My haematologist has stated in the past that my liver is fine, I have an appointment next Thursday so will put some questions together for him..The Mithridates trial was a third phase trial for Rux versus BAT either hydroxy which was what I was on at the time or interferon for PV patients. I was very lucky and allocated Rux which I desperately needed for the itch. Towards the end of my 3 year participation Rux was approved by NICE for PV patients who could not tolerate first line meds, so I am still on it . It's been great for the itch but the burning, tingling in my legs has never gone.

Once again thank you and others who have responded.

[Bullace]

Thank you very much for pointing me to this article, which was a really clear explanation of bone marrow fibrosis and has made me understand MF a bit better.

[George1976]

I’ve started taking fish oil to help my antiphospholipid syndrome. Mostly as an anti coagulant but I’m hoping its anti inflammatory properties will be beneficial as well especially as it relates to progression beyond ET. Previous tests on my inflammatory markers have been negative which has surprised me because I feel so sick most of the time.

[EPguy in reply to George1976]

I also take fish oil for my Sjo. But it and so many other supplements are blood thinners or anticoagulants, so I have to limit the oil.

Same here on the inflam test, esp CRP I've been normal range. Autoimmunes are notorious for feeling awful with normal bloods. Usually at least some more obscure tests may be abnormal. My LDH was high at DX but has declined to normal on Rux.

[TLJ-1]

Thanks for posting, EPGuy. That IL-1β is a major factor in MF progression has been known for some years now. Indeed, there is a monoclonal antibody canakinumab (Novartis via Ilaris) that targets IL-1β directly via subcutaneous injection that has been approved for some less-common autoimmune diseases. There is supposedly a clinical trial to try it in MF (NCT05467800), but I haven’t seen results of any testing. As far as I can tell, hematologists and patients generally are unaware that neurologists already know that IL-1β causes neuronal activation in the brain and subsequent fatigue, specifically a form of fatigue called “sick sleep syndrome”. Basically, it makes you want to go to sleep. I know from my own experience with this type of fatigue, so I did some literature search on the subject.

BTW, it has been known for a few years that IL-1β levels correlate with progression from PMF to PMF-BP [review: Baumeister et al Cell 10, 3551 (2021)]. But it is also known that IL-1β levels are higher with PMF than with ET or PV [review: Arranz Blood Reviews 31, 306 (2017)].

[EPguy in reply to TLJ-1]

Great detailed info, so my thought to look for this sort of agent was underway ~20 years ago. The Dr Méndez-Ferrer report should have introduced this very relevant info. His original research may be on the timing: "His research suggests that IL-1B’s influence is especially felt in the beginning of the progression towards MF"

This wording suggests anti IL-1β treatment while still in a pre MF state is most likely to benefit.

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This is the trial you refer run by a familiar name, Dr John Mascarenhas:

clinicaltrials.gov/study/NC...

Its primary completion is end of this year. But clinicaltrials is not always up to date, cancelled trials can persist on it. Let hope this one isn't, and gets a reason for phase 2.

But if Dr Méndez-Ferrer's work is relevant, this trial might have better results with pre-MF pts vs established MF.

One of the reports you refer suggests other anti-IL-1β agents are in the works.

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I relate to incentives to learn, I'm quite up to speed on Sjogrens. "sick sleep syndrome" sounds distinct from chronic fatigue that is the top Sjo Sx. But both share little with just "being tired".

[TLJ-1]

Good suggestion about anti- IL-1β strategies possibly being better for Pre-MP than for MP. However, IL-1β still appears to be a factor in progression to blast phase MP, which is nearly a death sentence. So … reducing the level of IL-1β could be useful for many of us even with more advanced MF.

You are correct that there are different types of fatigue, and I think many people do not recognize this. I believe the feeling is not the same with anemia, for example, and with MF.

BTW, reading what you wrote >1yr ago alerted me to the dangers lurking with Sjögren’s. In looking at the results from my antinuclear antibody report done at the time when I was being diagnosed with MF and knowing my symptoms, I self-diagnosed for Sjögren’s. However, it was such a minor issue in the face of the MF diagnosis, my hematologists never noted it, and I did not mention it to them. So, it’s up to me to make sure my treatment is appropriate.

[EPguy in reply to TLJ-1]

Agree reducing IL-1β at any point in an MF journey makes sense. We will get some idea next year when the trial is finished, But it's n is only 14 so it will leave room for more questions.

What symptoms brought you to a likely Sjo Dx? Sjo in males is uncommon (~10%) and on average has a more severe presentation. It also can be a cause of just about every and any malfunction and discomfort a whole body can acquire, fatigue of various sorts is a top complaint. Is it possible the Sjo is a signif contributor to your troubles? In my case the PV is background noise compared to Sjo, but MF is another level.

It may be worth a visit to a Rheum. A neurologist is also typical on a Sjo pt's list. A common med for Sjo is Plaquenil. It helps many, although I'm intolerant. There are no Sjo drugs now, but 5 drugs are in phase 3 right now that had good phase 2's vs zero till recently.

[TLJ-1]

With the only positive ANA test being for SS-A, having dry eyes, dry mouth, patches of dry skin, joint pain and prior history of a bad case of mononucleosis, I tentatively concluded that Sjögren’s was likely. Well, fatigue was likely there too, but that is pretty much swamped by the fatigue from MF. In the past couple years, it is also a little tricky to distinguish joint pain from the more recent bone pain, but I think I can tell the difference. I could not find any other disease that is consistent with the singular positive for SS-A.

As MF has been the major detractor in my quality of life, I have not really pursued any rigorous diagnosis for Sjögren’s. I do, however, appreciate your insights. If one of the new drugs you cite that are in phase 3 trials look really good, it might be worth checking this out further.

[EPguy]

I agree the Sjo Dx is right on. Lupus can have SS-a + but that is not relevant for your case. It can take many pts years to get the Dx, ours was easy.

One problem with the new drugs is all are immune suppressant to some extent. The best Cell trials all passed on Sjo for Lupus. So with Rux it might be a problem, hence my expectation I might have to quit Rux.

If your dry mouth is a significant problem there is a palliative, Cevimeline, that can help many quite well. I take a half dose.

I can relate, the disease that overwhelms most is the one we need to focus on.