new mutations

[Teachme85]

just had my second BMB a couple of months ago. Had been taking aspirin and monthly phlebotomy until 3 months ago when started hydroxyurea. My BMB now showed a new mutation IDH1 and allele burden increased from 24% to 52%. Didn’t need a phlebotomy this month but will be starting Besremi mid d June. Anyone else have this mutation? Really freaked me out when I read about it.

[hunter5582]

I do not have the IDH1 mutation, but do have another non-driver mutation, NF1. These non-driver mutations can influence the presentation of the MPN and risk of progression in different ways. The underlying molecular biology is quite complex. The understanding of the role these additional mutations play is improving.

The understanding of the significance of allele burden is also improving. This does appear to be a case of less is better in terms of symptom burden and risk of progression. The recent article by Moliterno et al does an excellent job summarizing the current data ashpublications.org/blood/a... .

Do note that the allele burden in bone marrow and peripheral blood can be different. It is important to compare blood to blood or marrow to marrow.

While it is unsettling to find out that a non-driver mutation is present and that allele burden may be progressing, you have taken an important step to do something about it. Besremi has demonstrated efficacy in not only managing PV, but in potentially improving progression-free survival. The Moliterno article addresses some aspects of this issue.

There are other things you can do to improve quality of life and potentially reduce risk of progression. Controlling inflammation is an important aspect of managing MPNs. There are different approaches to reducing inflammation in the body. There is some support in the research for the Mediterranean Diet. Some of us have had success with supplements like curcumin and NAC. Consultation with an Integrative or functional Medicine doctor can be very helpful if you re interested in pursuing any of these complementary health approaches.

To borrow the thought behind the Serenity Prayer, when managing a MPN we need the Serenity to accept the things about the MPN we cannot change; Courage to change the things that we can change; and Wisdom to understand what our options are and make good choices about our MPN care.

Wishing you all the best in the next stage of your MPN journey.

[Teachme85 in reply to hunter5582]

thank you for the info. I will continue to keep a clear mind and positive attitude as I start my new medicine protocol. I have extreme faith in my Mayo doc which really helps as I venture into these new waters.

[hunter5582 in reply to Teachme85]

While we each respond differently to each of the treatment options, I would note that Besremi has been very successful for me. I am maintaining a complete hematologic response at a low dose (150mcg). My allele burden has dropped from 38% to 9% in 18 months on low-dose interferons. Side effects have been minimal (mild itching/rashes, mild lymphopenia). My quality of life has improved. I feel better now than I did 10 years ago.

Wishing you similar success.

[Annula in reply to hunter5582]

Dear Hunter -You are such an inspiration & offer some sanity to those of us given these problems....I hope Teachme85 is reassured by your words of wisdom, knowledge & encouragement, as am I. Do you know how often a clinician should request a further BMB?I had just the one over 2 years ago..& have been on Hydroxy low dose since diagnosis... Your comments on an anti -inflammatory diet are food for thought too:):)... best wishes everyone.

[hunter5582 in reply to Annula]

Thank you for your kind words.

The frequency of repeat BMBs would vary based on your situation and the treatment preferences of the provider. Some docs do them more often than others. I think most would repat a BMB is there was a significant change in the status of how your MPN presents. Unless there is a reason to do so, most docs would not repeat a BMB as it would not be medically necessary.

My MPN Specialist will do a repeat BMB only when there is a clear reason to do so. We monitor my MPN status using blood work, current symptoms and periodically checking allele burden. We will not do a BMB unless there was evidence of progression. There is nothing that a BMB would tell us that would change my treatment plan. I am fine with approaching monitoring my status this way.

Hope that answers your question.

[ainslie in reply to hunter5582]

Hunter you wrote “there are other things you can do to improve quality of life and potentially reduce risk of progression”, you talk about reducing inflammation etc.

We have discussed this before , I agree we can do lots to improve quality of life but currently there is no evidence that anything we do (apart from possibly taking some drugs and that’s just a maybe for a minority) that can reduce the risk of progression unfortunately.

[hunter5582 in reply to ainslie]

There is a preponderance of evidence supporting the causative role of inflammation in both symptoms and promoting MPN progression. This is consistent with the research into the role of inflammation and other cancers. It is very reasonable to believe that reducing systemic inflammation is a good thing for anyone with a MPN. Given the role that inflammation plays in MPN progression, it is reasonable to believe that reducing inflammation would potentially reduce the risk of progression.

How to intervene is under active investigation. There are promising options that have the potential to make a significant difference. Unfortunately, interventions like diet and supplements are difficult to find research funding for. There is just not that much money to be made by promoting living a healthier lifestyle.

The role that inflammation plays in MPNs is well documented in the literature. Here is just a bit of what is available in the literature and in the MPN Space.

“Taken all together these evidences suggest that MPN is as a chronic tumor model driven by inflammation [64], in which chronic inflammation plays a critical role in the development and maintenance of MPN itself.” ncbi.nlm.nih.gov/pmc/articl...

“Despite the genetic component of MPN, inflammatory processes that modulate the BM microenvironment and affect both the malignant and physiological HSCs seem to contribute to disease pathogenesis and progression.” mpn-hub.com/medical-informa...

“Hematopoietic stem cells (HSCs) maintain an organism's immune system for a lifetime, and derangements in HSC proliferation and differentiation result in hematologic malignancies. Chronic inflammation plays a contributory if not causal role in HSC dysfunction. Inflammation induces HSC exhaustion, which promotes the emergence of mutant clones that may be resistant to an inflammatory microenvironment; this likely promotes the onset of a myeloid hematologic malignancy. Inflammatory cytokines are characteristically high in patients with myeloid malignancies and are linked to disease initiation, symptom burden, disease progression, and worsened prognostic survival. This review will cover our current understanding of the role of inflammation in the initiation, progression, and complications of myeloid hematologic malignancies, drawing from clinical studies as well as murine models. We will also highlight inflammation as a therapeutic target in hematologic malignancies.” europepmc.org/article/pmc/5...

Here are a few of the presentations where inflammation and its role in MPNs is presented and some of the potential interventions are discussed.

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

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

youtube.com/watch?v=Dh0H418...(Not working as expected?)

All anyone can do is to manage symptoms the best we can and improve the odds of progression free survival. It is very reasonable to believe that reducing inflammation improves quality of life and improves the odds of progression-free survival. There are no guarantees, but interventions that have little risk and significant potential benefits are always worth pursuing.

All the best my friend.

[ainslie in reply to hunter5582]

Some interesting links provided, the conclusion summary from the ncbi one says

"Available data are not sufficient to fully establish the role of inflammasome in myeloproliferative neoplasms (MPN) and further studies are needed in order to clarify such a role. However, it was shown that there is an inflammatory-state-driving MPNs and that the available drugs (i.e., JAKi), are effective and improve symptoms through the immune system regulation although they do not present curative potential when used as a single agent. A better understanding on the role of the inflammasome may provide new insights on possible therapeutic strategies."

in other words non conclusive.

You posted "There is a preponderance of evidence supporting the causative role of inflammation in both symptoms and promoting MPN progression." Well having read all you posted including links there is nothing there from a credible sourse confirming that inflamation promotes MPN progression but more importantly there is nothing there to confirm reducing inflamation will slow progression. Inflamation is not good for us generally for any health issue, I agree but there is no evidence to show it affects progression. I have been to many conferences and discussed it with many experts and never has anyone said if you reduce your inflamation your going to slow progression. It is also worth mentioning that it is the MPN thats causing most of the inflamation so if you can reduce the MPN load its logical inflamation may decrease but not necessarily the other way round.

You wrote "It is very reasonable to believe that reducing inflammation improves quality of life and improves the odds of progression-free survival". Well people are entitles to believe or hope or speculate as they wish but the medical facts remain the same which is a very different thing.

I attended that lecture by Angela Freischman at Phoenix, quite a interesting general talk but to say that the mediteranean diet etc produced similar percentage reduction in symptoms to Rux is frankly ridiculous. Clearly not the same bunch of patients in that trial. Anyone who tries Rux will confirm that the change in symptoms can be a life changer, and its well documented. I ate the med diet and saw many functional docs and had extensive detox, took all the right supplements under doc supervision and balanced hormones, and a lot more. During that time I itched like crazy, had visual migranes and plently other symptoms, I did all that for 10 years and my whites and platelets increased yearly , spleen grew a bit , all indicating progression. Since on Rux all symptoms except some fatigue gone , all counts in line , spleen normal. My expert says my CBC looks like I dont have PV , so comparing med diet etc to Rux is cuckoo.

For balance I think the med diet and exercise and all the vits and lowering inflamation etc is a excellent idea and I follow it and I wish it would affect progression but at time of writing there is absolutely no evidence lowering inflamation slows progression, I wish there was evidence.

You will note that most experts will not even say any of the meds we are on (exception Dr Silver of course) slow progression, (see recent Clair Harrison Vid in May). None of the experts I have seen have said so , they say lowering allelle MAY be significant in some way but not all agree on that. So if our experts are so reluctant to state that even the best drugs we have affect progression clearly thinking reducing inflamation by med diet etc is going to reduce progression is simply incorrect. We have to be optimistic but realistic and accurate.

[hunter5582 in reply to ainslie]

Having reviewed the data and presentations, we seem to have come to different conclusions. Not too surprising. The MPN experts do not agree either.

While the evidence is not absolute, I have concluded that reducing inflammation has the potential to reduce the chances of progression. It certainly is no guarantee. Since reducing inflammation has definite benefits, it is certainly in our best interests to reduce it when we can, particularly when it can be done using means with little or no risk. The chance that it may reduce risk of progression is an additional hopeful consideration. We must sometimes make judgements about the data and make the best decisions that we can.

Hopefully, there will be funding for research to provide better data on this issue. We do need better data on the efficacy of reducing inflammation. Unfortunately, there is not much money to be made with diet and supplements. Funding is far more limited for this kind of research.

I am very glad that you have had such a positive experience with RUX. It is becoming increasingly clear that there are significant benefits to the JAK-inhibitors, possibly beyond superior symptom control. I have had a similar experience with Besremi. I have achieved a complete hematologic response and my allele burden has dropped from 38% to 9% on a low dose (150mcg). My quality of life has improved significantly because of this treatment approach.

BTW - I agree it makes no sense to treat diet/supplements as though they are an alternative to a medication like ruxolitinib or Besremi. A Med Diet + supplement(s) would not provide the same level of symptom control, CHR or reduced allele burden. The use of diet and/or supplements should be considered a complement to treatment with medications with proven efficacy.

The debate over allele burden is ongoing. It is another important area for the MPN community to learn more about. The MPN Specialist I consult with believes that a reduced allele burden is a good thing, we just cannot prove how good yet. If you have not seen it yet, the recent review article by Moliterno et al has a very interesting update on this topic. ashpublications.org/blood/a...

Please do continue to provide alternate views on all MPN issues. It is through discussion and debate that we all learn.

Wishing you all the best on your MPN journey.

[ainslie in reply to hunter5582]

thank you , wishing you good health also, although we may have different views on a few things I think you do a good job on here helping others

[Aldebaran25]

You may find interesting and useful watching the video that Maz posted today "Video of the MPN Voice patients’ virtual forum 25 May 2023, Genetics and MPNs". It starts with some basic info on genetics initially, but then delves right into MPN mutations and the currently known clinical relevance. Basically, it is a very, very complex scenario and prediction on individual outcomes is still quite elusive as it depends on so many factors.