(Originally posted by Hunter) "Recent forum presented by our friends at MPN Advocacy & Education International"

[EPguy]

Hunter found this presentation:

healthunlocked.com/mpnvoice...

Great find. I went through the videos and have some notes/comments. I figured a top post should be most helpful.

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Dr. Raagit Rampal:

Lots of overlap in the 3 MPNs. MDS and others also have overlap.

ET does not have altered cellularity. (This conflicts with some other reports for example: "ET is usually characterized by a hypercellular bone marrow, including increased numbers of megakaryocytes." labce.com/spg761375_diagnos...

Interaction of MPL and CALR is not understood.

Having fibrosis does not always mean MF, PV and other conditions can have it.

ET-PV-MF trend in order to higher number of mutations.

Clotting is top risk in ET, similar in PV.

BMB is required to know whether PreMF or ET. PreMF is known starting in 2008.

Major changes are coming in treatments

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Dr. Linda Resar:

She notes the familial connection of MPNs. This idea is getting more accepted.

She studies HMGA1, inhibiting it is very promising. We will likely hear about it more.

She on this report: "HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML."

pubmed.ncbi.nlm.nih.gov/352...

It can stop growth of mutant cells. Silencing HMG also increases effect of Rux.

DFPROTACs can go after Hmga1, maybe a basis for future drugs.

Separately she notes IFN causes mutant cells to self renew too many times and wear out. I've posted on this before.

-Images here show effects of HMGA inhibition. In the left plot, it causes the orange points to reduce to the green ones, matching the blue non-mutated Jak2. Mouse spleen gets very reduced on the inhibitor.

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Dr. Andrew Kuykendall

Discussing new drugs.

On MF:

-Pactrinanib gives better symptom benefit than Rux.

-Momelotinib has deep R&D behind it. Good spleen and anemia response. Rux causes permanent Hb reductions, anemia. Momel is best Jak-i for reducing transfusions.

-Navitoclax is related to a leukemia drug. Improve spleen in Rux pts with large spleen.

-Pelabresib for further spleen reductions and symptoms.

-Blocking Jak-Stat, a central part of our disease, is only a partial fix since the disease finds alternate routes, this is the problem with Jak-i's and favors combo therapies.

-Luspatercept allows RBC to mature, add to Jak-i for anemia. 30% of Rux pts no longer needed transfusion.

-Imetelstat is different, a telomerase inhibitor. Increased OS in high risk pts. Not for spleen improvement.

Now there are many options beyond or after Rux.

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Symptoms

Pts often are told "your symptom is not MPN related." Drs ignore it bec they can't fix it.

Bone pain occurs in all 3 MPNs.

Cytokines are created in MPNs and cause our symptoms. There are too many types to target them easily.

Main symptoms that affect QoL are Fatigue, Concentration trouble, Depression.

Jak-i effects on MF symptoms: quick improvement on Rux.

Rux is not good for fatigue improvement in PV, ET while for PV, Pruritus, Sweats, Bone Pain are helped by Rux.

Rux is good for spleen.

Momelot and Rux are similar on symptoms so symptom is not a good reason to switch.

Fedratinib may help symptoms more.

Rux is not approved for ET bec it did not work well. ET is less cytokine affected. But itching was improved a lot.

HU and PEG on symptoms: minimal benefit with both. High baseline has more benefit. Latest data on Daliah trial supports lack of symp benefit for both. (In Conti-PV trial symptoms got worse on both HU and IFN but cohort had low burden to start) I can say I've had only minimal symp improvement, I think NAC supplement helps more here but no proof.

Plb is old fashioned. Resfertide helps here, stops phlbs. Rusf may help symptoms, but does not go to the source.

Ropeg is great on VAF, and is better tolerated than prior IFNs. But he hopes to hear more on symptoms at ASH 2022.

Non-drug treatments are best for fatigue. Sleep, diet, yoga etc. Dr Mesa is an expert here. (NAC supplement is discussed in this context in many posts on the forum)

ASH 2022:

RuxoPeg. Trail on this combo, maybe we'll have FDA approved access to it some day.

Current trials pay more attn to symptoms.

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Dr. Chi Joan How

Main MPN risk is thrombosis and cardio, but pts worry most about progression.

CHR and allele reduction are correlated. (many posts on the forum about this)

Bes has better CHR than other IFNs.

Still no certainty whether lower allele is useful.

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Dr. James Rossetti on SCT

-There are two types of SCTs "Autologous: Auto means self. The stem cells in autologous transplants come from the same person who will get the transplant, so the patient is their own donor. Allogeneic: Allo means other. The stem cells in allogeneic transplants are from a person other than the patient, either a matched related or unrelated donor."

-I've posted before that an auto transplant seems should be better, but he explains: For "various" reasons MPNs cannot use Auto transplant, we need Allo. A big reason is allo creates an immune response and this response is used to good effect by transplant Drs. Likely very complex details.

-"Reduced intensity" transplant has allowed older patients. Age is not the issue, health is.

-They can now manipulate donor cells so it's easier to find a match. Donors no longer need to be as close a match as before so near all can find a donor.

-Donor used to come from marrow, now easier via blood. They can get more cells via blood so faster benefits.

-Need good risk estimates to decide on SCT.

-ASXL and emergent mutations are risks.

-More miserable procedures (prep, drugs...) can give better odds.

-50% success rate for SCT is double that of 10 years ago.

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Ann Brazeau MPN Advocacy & Education International

She's never seen anything like this (current progress) in any other disease group.

Women MPNs are more prone to migraines and IFN helps.

Life expectancy has completely changed for MPNs.

If you have surgery, bring your team, esp hematologist etc. Plan your meds carefully.

She suggests keeping a wallet card with Dr, med info.

MPNs are less an orphan disease since more pts are presenting.

[Rem31]

Thank you! That’s really helpful.

[Poppy6060 in reply to Rem31]

thank you a helpful read

[Mostew]

Thank you so much for explaining clearly for those of us that would get bogged down with to much detail. I Do appreciate your efforts..

[Aldebaran25]

Thank you EPguy!

[Solyesh]

Thank you! Quite helpful. The discussion by Dr Rampal mirrors my most recent appointment with my MPN specialist as I was trying to pinpoint if we are dealing with preMF or ET. He, my specialist, always emphasizes the continuum nature of MPNs; how they are interrelated and how they overlap. Interesting statement on hypercellularity as I too have seen contradicting studies - will have to go back and have another look.

[EPguy in reply to Solyesh]

On cellularity, one idea is there are narrow and broad ways of considering it. The narrow one focuses on excess RBC precursors as would be expected in PV. These are probably the dense light pepper looking things in the BMBs. A broader one looks at all precursors as in my example above where PLT precursors megakaryocytes are included. This could be expected in ET.

This images here I think are good examples:

centralcoasthaematology.com...

The upper one is the pepper looking things, the lower is excess Karyocytes. (my interpretation)

Hypercell

[Rita-Lou]

Thank you