Update on MPN Status and other items

[hunter5582]

The results of the MPN Myeloid Panel are in. The good news is that I am negative for all of the non-driver MPN-related gene mutations (see list below). They did detect the two known mutations on this panel JAK2:c.1849G>T (aka JAK2v617f) and NF1:c5425C>T. One point of curiosity is that on this panel I show with a JAK2 mutant allele burden of 29% where a month earlier I showed with 26% on a different lab. The year before I was at 25%. Not sure of the significance of the 26% vs 29%, but suspect it is likely just an artifact of the variance between the different lab techniques (or within the margin of error). Will check with the docs on this.

I have had an oddity in that HCT has been steadily declining since my last venesection on 8/26. Went from 43.6 on 09/08, to 39.4 on 9/28, to 39.1 on 10/28. Will be getting another CBC next week. We will see what it is then. Platelets have also been running consistently on the high side of my normal range (in the 700s) with that one odd spike back in July to 903. My two hematologists are aware and not particularly concerned at this point. Plan is to continue the venesection-only treatment protocol and monitor. I remain asymptomatic from primary PV symptoms and feel fine. Well, fine for an old guy with systemic inflammation, osteoarthritis. a bum knee, a bad back etc. etc. 😄 At age 65 with PV and NF1 - I am fortunate to feel as good as I do! I will take my blessings as they come.

I have not had any repeat incidents of the visual migraines or hallucinatory palinopsia. Either the cortical irritation calmed down on its own or the Magnesium dosing is working. I will take it either way. I was still showing a Mg deficient despite the old Mg dose, so changed form and increased dose. Will reevaluate Mg and Folate (also still deficient) in the near future. I am just thankful that it does not appear that I will need to initiate treatment with anti-seizure meds. Hopefully that will stay the case. I am getting fitted with prism-lenses for the convergence insufficiency so that should help further improve my vision.

So - all in all good news. Thanks to all my MPN brothers and sisters for your interest and support.

LIST OF ALL GENES IN PANEL

ABL1 CUX1 IKZF1 NPM1 SF3B1

ASXL1 DNMT3A JAK2 NRAS SMC1A

BCOR ETV6 JAK3 PDGFRA SMC3

BCORL1 EZH2 KDM6A PHF6 SRSF2

BRAF FBXW7 KIT PML STAG2

CALR FLT3 KMT2A PTEN TET2 CBL GATA1

KRAS PTPN11 TP53 CDKN2A GATA2 MPL RAD21 U2AF1 CEBPA IDH1 NF1

RUNX1 WT1 CSF3R IDH2 NOTCH1 SETBP1 ZRSR2

ps. I really believe that the MPN Myeloid Panel and Mutant Allele Quantitative Analysis should be a standard of care for everyone with a MPN.

[dladydi]

Good news Hunter. Thx for the update. All the best from Canada.

[BeHealthy1986]

Hi Steve, I am happy for you. The comprehensive myeloid panel testing results looks real good. No surprise is good news👍 It’s also good to hear that you don’t have primary PV symptoms.

Last month I tested for 17 myeloid genes and no mutation was found. This month I had a second genetic testing called MSK-IMPACT and waiting for the results. Does genetic testing results often show the allele burden for the mutated genes? The MPN specialist I am seeing also emphasized the importance of molecular study in treating MPN.

-YC

[hunter5582 in reply to BeHealthy1986]

Some testing does show the allele burden (quantitative) but not all testing does (qualitative). It depends an what was ordered/available. Glad to hear you have a MPN Specialist who is paying attention to these issues. That is how it should be for all of us with MPNs.

[socrates_8]

Great news Hunter...

And I couldn't agree more w/ your sentiments. Hopefully, (even if only here in Australia), we might be moving the way of making all such tests within the reach of all and sundry etc...

Stay safe & well buddy....

Steve

[hunter5582 in reply to socrates_8]

I hope the testing does open up for y'all in Australia and everywhere else. It really should be a standard of care.

[socrates_8 in reply to hunter5582]

Hey Hunter...

Yes, you may recall an earlier Post I had out there concerning 'Alelle Burden Frequencies' (ABFs), and the fact that at the present (Here in Oz), Only JAK2 ABFs were being recorded, and that they could be obtained relatively inexpensively.

However, NGS, cost $500.00. There are moves afoot here now to try to have some equity for people who have one of the other Two (2) Driver mutations, (i.e. MPL & CALR), because unless they have a panel NGS, they would not ever find out what those ABFs might have been etc...

I agree w/ your sentiments of course, NGS & ABFs, should be made available for all MPN patients ...

Fingers crossed buddy...

Steve

[hunter5582 in reply to socrates_8]

It really is important information. It is possible, though not common, to have more than one driver mutation present. It is also quite possible to have one or more of the non-driver mutations present on top of the driver-mutation.

Hopefully as the cost of NGS assessments drops, more people will be able to access appropriate diagnostic testing. It really does inform treatment decisions.

[socrates_8 in reply to hunter5582]

Agreed buddy...

But there are dragging their heels for the minute bringing these changes about, and that's if indeed they do come at all... (?)

Yes, I am aware that one might be say MPL or CALR & later also have JAK2 detected. Not so sure that it ever happens in reverse however... (?)

Pleased for you that they did not find anymore bad news for you Hunter...

Steve

[hunter5582 in reply to socrates_8]

I do believe it can go either way. I suspect the mutations could be acquired at the same time or as different genetic events.

I did see an interesting presentation speculating that these mutations (transversions) could be the result of quantum tunneling. Very interesting theory, Way over my head, but interesting none-the-less.

Looking forward to the next Cafe Catch Up. See you then

[socrates_8 in reply to hunter5582]

Cheers buddy...

Yes, me too... Still wrestling with my FORUM Updates down here at the present moment, and will hopefully have it all sorted again soon... Fingers crossed(?)

Then I'll spend a few moments w/ our ZOOM 'Invites' etc...

Later

Steve

[NedKel65 in reply to socrates_8]

Hi Hunter and Steve I’m blown away by your knowledge and recognise a few things that were discussed with my initial diagnosis of ET

I have JAK2 positive and CALR which was determined after bone marrow biopsy

I was told it’s a rare occurrence but know little more than that 😊

Very interested in your conversation as I said before I still know very little about MPNs

[hunter5582 in reply to NedKel65]

That is extremely rare. It used to be thought that it never happened, so the docs never bothered checking once they had a positive JAK2. My former MPN Specialist, Dr. Spivak, told me that it does indeed happen. I have had the NGS study done and have the JAK2v617f and NF1:c5425C>T mutations.

Most of what I have learned about has been regarding the role of non-driver mutations in MPNs. The additional mutations can affect the presentation of the MPN in significant ways. I would expect it to be the same if you have two driver mutations.

I did a quick look and found a few articles you may be interested in. Some of the material is very technical. Be prepared to do some secondary reading if you do not already have a medical background.

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

onlinelibrary.wiley.com/doi...

ashpublications.org/blood/a...

It is very important to have a MPN Specialist involved on your care for any MPN. More so when you have an unusual presentation. Most hematologists simply lack the KSAs to provide optimal care even for "regular" MPNs. Just in case you have not seen this here is a list. mpnforum.com/list-hem./

There is a good place to start building knowledge in these presentations.

MPN Molecular Biology

youtube.com/watch?v=zHwTIJb...(Not working as expected?)

MPN Education Foundation 2021 Presentations

mpninfo.org/conferences/202...

I hope this helps you as you begin this rather interesting journey. Please expect your MPN journey to be a long one, filled with learning and developing a knowledge base to successfully manage the condition.

All the best to you.

[Bridie123 in reply to hunter5582]

Not all of us in the UK have these tests do we?

[MaggieSylvie in reply to Bridie123]

It makes me wonder, as I've been told I don't have any gene mutations. Could it be that I just don't have the major three?

[hunter5582 in reply to MaggieSylvie]

There are additional mutations under investigation that are the likely drivers for people who are triple-negative. Hopefully we will all know more in the future.

[MaggieSylvie in reply to hunter5582]

Well, I don't know. It's good that they are investigating but does it help to have a mutation? Mutations are not being treated, are they, other than specific medications to ease any nasty symptoms? What we need is mutation reversal.

[hunter5582 in reply to MaggieSylvie]

Ultimately understanding the underlying genetics will allow the development of more targeted therapies. This is the area where cancer treatment is becoming far more effective. There is an immunotherapy that targets cells with the CALR mutation that sounds promising. It does not work for the JAK2 mutation because JAK2 mutated cells are more difficult for the body to identify as abnormal. (CALR mutated cells have a detectable difference in the cell wall).

The closest thing we have to mutation reversal at this point is PEGylated Interferons. Molecular remission is when there is not longer detectable mutated hemopoietic stem cells (HSCs) present in the body. These mutations are somatic mutations and not present in our germline DNA. Getting rid of all of the abnormal HSCs while leaving the wild-type (normal) one behind is the ultimate goal of treatment. It is not understood why some people attain molecular remission while others do not. I think it is almost certain that it has to do with the underlying genetics of each persons MPN.

[Manouche in reply to hunter5582]

Hi Hunter,

May I ask you why you still prefer the venesection treatment, knowing that INF could potentially induce a molecular remission and an operational cure in your case ?

[hunter5582 in reply to Manouche]

Venesection-only is the recommendation from my MPN Specialist and regular hematologist based on my presentation of PV. I have a relatively indolent form of a MPN. As promising as PEG-IFN is, it is not without its own risks. Based on my own assessment - venesection only is the right choice for me - for now.

I am actively considering PEG-IFN and tracking the research as it continues to unfold. I also find some of the combination therapies quite promising. I am hoping that Besremi will be approved in the USA soon. Working with my care team, we have already decided that we will move to PEG-IFN if there is any evidence of disease progression. That is why I opted to recheck the allele burden and run the myeloid panel.

I may still opt for PEG-IFN proactively at some point. I am open to it, but not ready just yet.

I am also waiting for the hepcidin mimetic PGT-300 to be approved. I will almost certainly opt for that when it becomes available. While manageable, I do find some aspects of chronic iron deficiency bothersome. It would be good to have another option to control erythrocytosis.

All the best my friend.

[hunter5582 in reply to Bridie123]

Not sure about the UK. The tests exist - it is a matter of whether the NHS will let you access them. I know that in Canada, they do not have access to the tests though their national health system.

[Mostew]

I am pleased to read your update .

I do think glass half full approach to life is so much more beneficial to our health than half empty . !

I send you my blessings

And warm wishes

[hunter5582 in reply to Mostew]

A glass half-full can still quench your thirst. I glass half empty leaves you thirsty. It is all a matter of perspective.

[Mostew in reply to hunter5582]

So is it better to be half full ?

[hunter5582 in reply to Mostew]

Much better 👍

[Scrollernut]

Didn’t understand much of what you said but if it’s good news I’m very happy for you. 🤩. Happy thanksgiving 😍

[hunter5582 in reply to Scrollernut]

Happy and Blessed Thanksgiving to you too. 🙏

[Cja1956]

Glad to hear your test results were improved and that, overall, your doing pretty well. It’s so nice to hear something positive! Stay well and thanks for sharing your good news. I’ve never had a myeloid panel, and like Scrollernut, I don’t understand what it all means, but you never fail to educate me. Best wishes and Happy Thanksgiving!

[hunter5582 in reply to Cja1956]

Short version = driver mutations like JAK2v627f (and JAK2 Exon 12, CALR, MPL) cause the MPN. A larger mutant allele burden makes it worse. Non-driver mutations (e.g. NF1, ASXL1, TP53) can also make the MPN worse. This is case where less is better.

Having the NF1 mutation on top of the JAK2 mutation makes my risks higher (e.g. risk of leukemic progression). Thus not having any other mutations is really good news,

[Cja1956]

All I know is I have Jak 2 V617F and KRAS a146v mutations from my SCT last year. My Allele burden said 63.5%. Looking at it now, it says it’s a Myeloid Disorders Profile. So I guess I did have one. That’s when I was diagnosed with post ET MF. I knew about the Jak 2 mutation in 2008, but I had never heard of an allele burden until last year. And I definitely never heard of KRAS or if it even means anything. Anyway, if you can make heads or tails of this, that would be great. Take care,

Cindy

[hunter5582 in reply to Cja1956]

The short version is that the KRAS gene mutation can cause multiple types of cancers. It causes deregulation of the RAS-MAPK pathway, one of the body's kinase systems. The kinase systems regulate cell growth and other body functions. RAS-MAPK is downstream from the JAK-STAT pathway and is involved in MPNs. Having both mutations can amplify the MPN and make progression more likely.

I also have two mutations present. JAK2 (JAK-STAT pathway) and NF1 (MEK-ERK part of the RAS-MAPK pathway). Understanding how these multiple mutations interact is quite complex. We know that they do, but not always exactly how. I have asked my very knowledgeable MPN and NF specialists this question and they always say "That is a very good question." No clear answer though. I do understand that JAK2 + NF1 mutations increases my risk of leukemic progression. That does not mean it will happen, just that it is more likely than with one mutation alone. Understanding my own risk profile better is why I had the Myeloid Panel run. It will inform my treatment decisions.

Proteomics (study of proteins) is quite complex. I am only dimly beginning to understand it. Bit by bit I am trying to learn more. Here are a few of the relevant resources I have looked at.

KRAS

en.wikipedia.org/wiki/KRAS

KRAS

cancer.gov/publications/dic...

JAK2 + KRAS

pubmed.ncbi.nlm.nih.gov/206...

JAK2 + non-driver mutations (does not include KRAS but informative)

ashpublications.org/blood/a...

ashclinicalnews.org/news/ne...

KRAS

mycancergenome.org/content/....

[Cja1956 in reply to hunter5582]

Thanks so much for your reply. As I’ve said before, you are a wealth of information and I always learn so much from you.

[IrishHiker]

Always great to receive good news. Stay safe and happy.

[Bridie123]

Glad to hear you are keeping well 🤗

[Wyebird]

Many thanks for keeping us informed. I’m ashamed to admit some of it is over my head.I do gather that for you it is all positive and that is the main thing.

I do hope you continue to feel well.

[Kiki64]

Hi Hunter

This is very reassuring news for you. Yes I Agree that they should be the standard of care for everyone who has a MPN

Best wishes

Kiki ☺️

[Hidden]

Hunter i always thought you were girl!! Haha love reading your very informative replies. Very well informed. You have helped me here in NZ on numerous occasions. Thanyou. I am slighty older than you with ET CALR. My 6monthly bloods due next month. Very keen to see if 920 was just a blip and I like you go back to 700. Here's hoping!! Going back to the same lab as the 700 result!!

[hunter5582 in reply to Hidden]

Nope. Definitely a guy! LOL.

Do hope you 900 was a blip like mine was. We do all have those blips. Platelet level can jump by as much as 100K in 1 day depending on what is going on in your body. It is really more about the symptoms than the numbers, but it nice when the numbers are lower. Hope you get good news.

[Jazzyb50]

Good news Hunter and thanks for the update. Take care 😊

[Windy51]

All the best Hunterxx

[Hidden]

Fascinating Hunter and very positive news for you. Motivated by your experiences l called today and got my second opinion appointment for Monday ( amazed how quick) with the Professor himself at the MPN clinic Charité in Berlin. I will hopefully get to ask lots of questions based on all the knowledge l have acquired from forum members

[hunter5582 in reply to Hidden]

That is outstanding! I hope you get all of your questions answered. This really is the best way to ensure your receive the highest possible quality of care. Please let us know how it goes.

[azaelea]

Good to hear, Hunter. Keep on keeping well! Best wishes, Fran

[elliebongo]

Best wishes Hunter - the positivity in your messages always uplifting. Keep well. Just realised obviously not intelligent enough to understand everything you say. But rather cool you are so knowledgeable. Thanks for all your comments

[SilverET]

Hi Hunter,Sounds like great news to me. More info is always better in my opinion so that rational treatment decisions can be made by both the patient and physician. It sounds like you are in a good place at the moment and fingers crossed it continues for you. Wish we could get tested easily here in Oz for all the genetic markers in a quantitative manner.Regards,

SilverET