Oh that's so great, congrats! I was at 60% when diagnosed last year. I was trying to follow some of the discussions on allele burden on this site, and it seems the lower the better, but it also didn't seem100% conclusive? However, it does seem that interferons are effective at reducing the % and that this could stop the MPN from progressing, is that correct? I did ask my hematologist about Besremi recently and he was still of the view of "wait and see". I am currently on Jakafi. I will ask him again when we next speak and try and read around a bit more. I am excited for you, Hunter!
There is still debate about the significance if variant allele frequency. Part of the issue is that a higher VAF TENDS to be associated with a higher symptom burden and disease progression. We know that people with ET tend to have the lowest VAF, people with MF the highest, and people with PV somewhere in the middle. It is still being debated about the value of reducing allele burden since the pathogenesis of MPNs is not completely understood.
I think Dr. Kalajiian summed things up rather nicely in his Tweet. "Please experts, help me... are there hematological malignancies where reducing the driver mutation is not clinically beneficial? I'm confused, this is disputed for PV and JAK2 mutation, so finding another example could be helpful... I can also take examples in solid tumors..."No one seems to have an answer to his question.
One thing I am certain of - I would much rather see the VAF go down rather than up. The great hope with Besremi is that what was seen in research will be seen in clinical practice - progression free survival. More cases of molecular remission would be a great secondary endpoint.
That's a good quote. Implication is there are other hemo malignancies that have demonstrated a benefit with VAF reduction. Has he identified some? If so he's right it is inconsistent to hold MPN to a different standard.
I thought the consensus was that rising AB was a significant progression risk as well as stroke risk. Dr. Kalajiian defines remission as JAK2 AB under 10% and he must have the data to back this up.
I wonder if the issue is what caused the JAK2 reduction? eg HU, Ruxo or INF? Only INF can deliver possible remission?
Neat concise info. This follows the CHR vs VAF concept:
"The JAK2 V617F allele burden was correlated with hematologic parameters"
and "JAK2 V617F allele burdens were positively correlated with white blood cell counts, hemoglobin values, lactate dehydrogenase levels, and platelet counts. "
In the plots there is a strangeness, having VAF < 30% is worse for TFS vs <58%. But P values for 30% are bad, so best to consider the 58% cutoff as most valid.
Following the link for the article gives the abstract which you enlightened us about. Thanks! It also contains the charts with explanation: The 58% data is for PV and 30% data is for ET. It is very interesting to see that the risk of Thrombosis is higher with ET than PV and the 30% cutoff level is not that meaningful. It begs the question of whether there is a lower percentage below which the ET thrombosis risk is significantly less.
Agree on the (lack of) conclusion. It does seem getting to at least one of: less than 10, 2 and 1% have certain benefits from the various reports discussed here.
Jakafi can also give allele reductions, see plot here. But it's not as dramatic as the plots we see for IFN, the green (Rux) and blue (best avail other than Rux) are not so different. I've seen others a bit better than this but still not matching IFN. Rux does have other benefits of course.
Please take a look at both Hunter and EPguy's posts referencing Dr. Silver's talks about PMNP's and IFN's, and maybe mine about Dr. Mesa's re: the same.
I really needed to jumpstart my Heme/Onc's motor to get my change frrom HU to Besremi, and the literature about Jakafi's effect on limiting disease progression isn't much, if any better than HU's. I forwarded a bunch of research papers just to get her to agree with my going to Roswell Park to see an actual MPN specialist.
Also, if your hematologist isn't specifically an MPN specialist, you might want to look into getting a consultation or second opinion from one.
This site has a list of MPN specialists recommended by their patients.: mpnforum.com/list-hem.
With a drop like that you're looking promising to be in the 21% of pts that get to less than 1%, and lets hope well before the 6 years this familiar report was from.
I am hopeful that I will be amongst those that achieve VAF < 1%. Time will tell. I do find it interesting that the highest IFN dose I have used is 150mcg Besremi. It is a good case example that achieving CHR may be what really matters.
I have been taking curcumin for quite some time now (8+ years), originally recommended by my rheumatologist for osteoarthritis. I have been taking the L-Glutathione for a couple of years as recommended by mu Integrative Medicine doc as a NAC-downstream alternative. I am also taking a pro-resolving mediator (fish oil derivative) - SPM Active. I do believe that doing what we can to control systemic inflammation if very important.
I recall we discussed before, was there a specific reason your consultant recommended L-Glu over NAC? I recall Glu requires the right form to be active.
The Integrative Med Doc said that the benefit of NAC is that it increases L-Glutathione in the body. I use the specific forumation that she recommends.
I suspect that the reason NAC is being looked at is that it is effective as an anti-inflammatory agent and it has an FDA approved use in the USA. I beiieve someone else posted about this.
Does it seem right that your Doc considers either to be equivalent for providing active Glu? Or might direct Glu be preferred over NAC?
In either case, your result is more evidence that as a minimum, Glu does not prevent the allele reduction benefit. There was a brief concern from member Paul123456 that his NAC might have inhibited the reductions, but conclusion was it was just the PEG dose.
Another notable, might there be a specific correlation of strong WBC response on IFN to allele reductions? We both have low WBC and are seeing VAF reductions. More broadly, is the WBC portion of CHR of particular interest? I don't recall any studies following this thought. But I think I've seen that HCT is less essential part of CHR for allele reductions.
My Integrative med doc prefers L-Glut simply as a more direct path to the same goal. When there was a temporary L-Glut shortage, we shifted to NAC. She is very specific about the formulation for L-Glut. that definitely matters.
I suspect the reduction in WBC may correlate with reduction in VAF in the sense that reduction in leukopoiesis is part of achieving a CHR. I doubt there is a causal relationship between WBC reduction and VAF reduction, just that IFNs are doing both things. Not sure about reduction in erythropoiesis, but suspect it would be the same correlation.
hopefully we will all learn more with Besremi in broader clinical use.
My curiosity is up so I'm trying to learn more. Is all of this below consistent with your info?
--
It seems there is L-Glu vs just Glu. L is the reduced, active form. There's another unrelated L, for Liposomal.
In this report ca 2022: "Liposomal glutathione, on the other hand, is protected from the harsh environment of the stomach by the liposomes and is able to pass through cell membranes to be used directly within the cell"
So according to this the best form would be the double L type, Liposomal L Glutathione, assuming there is such a thing. If not, just Liposomal is the ticket.
Is this consistent with your Doc's info?
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This next article is from an integrative med doc, Joseph Pizzorno, . ca 2014. He seems big in the field:
Glutathione includes these relevant actions: "Regulation of cellular proliferation and apoptosis"
Toxins are relevant to our MPN condition: "Low levels of glutathione and/or transferase activity are also associated with chronic exposure to chemical toxins"
Oral has issues, but he agrees with the article above that liposomal glutathione is useful (and likely more proven since 2014) : "Oral administration is controversial; while most research shows that oral glutathione does not increase RBC glutathione, there are a few studies that show efficacy.28 My (Dr Joseph Pizzorno's ) opinion is that unmodified oral glutathione is unlikely to consistently elevate cellular levels. Oral and transdermal liposomal glutathione show promise, but research is early.29"
NAC solves the activity problem, and 1000/day is likely enough, but maybe the recent work on Liposomal has provided the alternate route: "While oral cysteine does not make it through the digestive track, (see exception above) supplemental cysteine in the form of whey or N-acetylcysteine (NAC) is effective at raising levels. While there is substantial variation, 1000 mg/d of NAC will substantially increase glutathione in virtually all patients."
I am taking proprietary brand of L-Glutathione manufactured for my Integrative medicine doc. I do not believe it is liposomal. I take 1 - 250mg cap/day. We did measure my serum levels after I initiated taking the L-Glut.
Total Glutathione 356 ug/mL High (reference range 176-323).
i would say this formulation is making it into my system.
FYI - this is the same thing through an on-line pharmacy. requires a doctor's order.
L-Glutathione Ortho Molecular Products
Product description
Glutathione is the master antioxidant in the body and is heavily concentrated in tissues such as the liver, spleen and heart. Therefore, it plays a crucial role in immune function, detoxification capacity and protection against oxidative stress. The L-Glutathione formulation is preformed, reduced glutathione (GSH) and provides a 250 mg dose in a one-capsule serving.
1 capsule per day or as recommended by your health care professional
Serving Size: 1 Capsule
Amount Per Serving L-Glutathione ... 250mg
Does Not Contain: Gluten, Corn, Yeast, Artificial colors or flavors
Cautions: If you are pregnant or nursing, consult your health care professional before taking this product.
Thanks for the detailed info. It seems the magic is the Setria brand of L-Glu made in Japan. From what I can tell this is what I called the double L type, being both L- Glu and Liposomal. So it's the good stuff.
"Setria is a Japanese brand of Glutathione we prefer to use in our products. The liposomal delivery system used in this product protects Glutathione and enhances its absorption into the circulation"
From what I see, Setria is used in Glu from more than one mfr. I expect the one you're getting has a better pedigree.
Until recently I think Glu was not available in this helpful form so only NAC was able to deliver it. Now there is this new and effective option, which your lab confirmed.
This discussion of liposomal Glutathione being better absorbed, and thus more bioavailable, was interesting to me, because in reading about the MRNA COVID vaccines, they were originally considered problematic because of the quick degradation of unshielded RNA in the body, but by coating them with a lipid coating [of liposomal origin], they are protected long enough to trigger the needed immune response.
Maybe the same goes for Glutathione in the GI tract.
Best,
PA
PS: For anyone [who like myself] isn't quite sure why there is all this discussion about Glutathione, here is an article in actual English that explains more:
This is so great to see!!! Like you say, the jury is out on this, but lower seems a heck of a lot better. Thanks always for sharing your journey and such helpful information.
hunter, great news! As far as VAF goes, I’ve been pondering a lot about it lately given my lack of reduction on fairly high doses of Pegasys. My understanding is the VAF comes from nucleated cells, which are WBCs, or maybe nucleated RBCs but those are typically found at end phase PV/transition to MF. The issue I’ve been wrestling with is my WBCs were much higher at diagnosis than now (11 or so vs 5-7 now). Yes the % of mutated WBCs may not have changed but the number of them is about half what it was so there’s fewer total regardless of the % of those fewer nucleated cells. For example a 50% AB with WBCs at 12 may be the same amount of JAK2 mutated cells would result in a close to 100% AB at 6. Maybe I am over thinking it but seems like if you have 50% AB with WBCs at 12, and 50% AB with WBCs at 6, this is not apples to apples, but may show progress.
I believe that VAF is determined by isolating DNA from hematopoietic stems cells obtained from either blood or bone marrow.
Success in n treatment that we have been discussing is in two parts. Complete Hematologic Response (CHR) = control of all three types of blood cells (RBC, PLT, WBC), keeping all in the desired range. Molecular Remission = VAF < 10% and Complete Molecular Remission = JAK2 mutation undetectable.
There is no question about the value of achieving CHR. It is the goal of treatment and reduces risk of thrombosis and hemorrhage. It prolongs overall survival even in the absence of a molecular remission.
« My understanding is the VAF comes from nucleated cells, which are WBCs, or maybe nucleated RBCs but those are typically found at end phase PV/transition to MF« .
It’s worth mentioning that red blood cells do not have a nucleus.
There can be nucleated RBC, but it is a sign of progression, MDS, leukemia or other such conditions. Makes sense they would not use it for allele since it is not normally present in blood.
I've tried to figure out this issue also. I think the way they get VAF from blood has evolved over the years and I think I've even seen use of plasma. The other way is from BMB. I got different results for blood vs BMB.
My specialist said the blood result is very accurate, but I still don't know how it happens.
Congratulations Hunter- I'm totally chuffed on your behalf- and this also makes me more optimistic on my own behalf. as well as reinforcing my need to be patient and await the good results as time passes.
May I ask what your current dosage is for Besremi?
When first diagnosed in June 2016 with PRV Jak2 + V617F at 59% .About a year ago I asked my haematologist if she could confirm that my AB had been reduced.She told me that no further check had been done on the AB as it was not important.I have been on 11 number 500mg Hydroxycarbamide for 5 years and wonder at what stage a check on my current AB would be appropriate I am now 81 years old.
I think it is unlikely that the Allele Burden will be reduced on hydroxycarbamide. It is at a certain level correct that there is no point to rechecking to see if AB is reduced since it AB will likely be the same or may have increased. AB can be used as a marker of progression but that is not evaluated on a regular basis by many hematologists. Suggest consulting with a MPN Specialist on the issue.
Note that I do consult with a MPN Specialist. We have checked my allele burden periodically to monitor status and performed the Intelligen MPN Panel to look at the presence of non-driver mutations too. My MPN Specialist wanted to check allele burden 18 months out from initiation of treatment with interferon. Some wait for 2-3 years.
The plan we have had in place regarding monitoring allele burden is that we would check if there was an indication of change in disease status like an uptick in symptoms. A significant increase in allele burden and change in disease status would trigger a bone marrow biopsy.
Note that many regular hematologists rarely treat MPNs. They are not up-to-date on the emerging research and evolving thinking regarding allele burden and other issues related to MPNs. That is why consulting with a MPN Specialist optimizes care.
As Hunter says, HU is not known for lowering AB. You can see in the plot above here in this thread with the grey and red lines. The grey line shows the AB on HU. It lowers in the 1st year or so but then the effect fades.
But I think many of us would disagree that AB is not important. Exactly how it's important is rapidly being studied. But it is looking likely to be worth knowing over time.
What wonderful news Hunter! You are such an inspiration and source of knowledge, I read everything you post! I’m in North Carolina & was diagnosed with PV in August 2021 JAK2 positive (22%) and have been on Hydroxy, aspirin and phlebotomies since then. My MPN Hem recommended Besremi in October and I will start it after the holidays. I’ve been nervous about it but this is such great news. I know we are all different but this makes me feel hopeful and gives me the courage to go for it. Thank you! And best of luck on your continued journey… please keep on posting those gems of wisdom!
I'm happy [for you] to hear that you're going to more active [disease-modifying] treatment soon.
Remember to be patient, as at least in my ongoing personal experience, there is definitely an adjustment period, and some necessary dose titration will be involved- especially when transitioning from HU.
I have to keep reminding myself that this is all a process, and not so much a specific delineated goal [well, except for CHR and hopefully CMR maybe].
Thank you Hunter for your prompt and reasoned response I will discuss with my haematologist on my next 6 weekly hospital visit at Northallerton North Yorkshire on 29/12/22
Good news! As you say, whilst there is debate what the significance is, if it wasn't there it would be good....so less is surely something to celebrate!
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Non driving gene mutation-ASXL1
