I have Pv. I was diagnosed in 2020 when I was 56. My Allele burden was then 67%. I have been on Pegasys for 1.5 years. I am now at the full 185 mcg due to the fact my numbers were not moving in the right direction. Thankfully my symptoms are mild and my numbers are getting a little better now. I had labs last week and my allele burden is now 87%. I was so disappointed . My doctor is an MPN specialist. Has anyone had this happen while on Pegasys?
Pegasys not working to lower Allele burden - MPN Voice
Pegasys not working to lower Allele burden
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Roxthebox
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Sorry to hear that your allele burden has not decreased. It is important to realize that treatment with Pegasys is a marathon not a sprint. It can take years to see full benefit. While there is no way to prove this, it is plausible that the PEG may be slowing down progression even though it has not completely stopped it.
Wishing you success moving forward.
Thank you. You too!
Hi, I have the same experience, with my JAK2 allele burden not going down but actually increasing after 18 months on Pegasys. Have switched to Besremi (due to moving country) in March and I am curious to see if it will have an impact. Haematologic control is good but allele burden 3 months ago was over 80%. I don’t worry too much about it, the haem told me to be patient and time will tell. I think at present knowledge is still patchy on the genetics behind our disease and many other non driver mutations are also at play. Like you, I have very mild symptoms, isn’t that counterintuitive should all be down to JAK2? All the best, I hope we both achieve good control !
Depending on family history and type of mutation, a variant allele frequency above 50% at diagnosis, especially in young-ish patients could suggest that a person has inherited the mutation. And in that case, Interferon treatment might not necessarily be very efficient in reducing allele burden, some studies were speculating on this.But most likely your MPN specialist can tell you more about your specific mutation and whether it is inherited or not, or what is the reason for your fast change in allele burden.
I have never heard of that, is that speculation or a fact
Higher allele burden and the suspicion that it can suggest an MPN is inherited is covered by scientific literature. And differences between some inherited MPNs and MPNs due to somatic mutations are also covered by scientific literature. MPNs can be caused by somatic mutations (mutations you acquired during lifetime and are present only in the affected cells), by germline mutations (they are transmitted from parents to children and are present in the DNA of every cell in the body, like all other inherited features) or by a combination of a germline and a somatic mutation. When the patient is rather young and has a variant allele frequency above 50%, a good specialist, based on the type of mutation, needs to ask family history of the disease and check for potential inheritance. There are also familial MPNs, where one does not inherit the mutation causing the MPNs per se, as much as one inherits the propensity to acquire that mutation during lifetime. This means that in the same family, the parent can have JAK2 mutation and the child has MPL mutation, but both have essential thrombocythemia. Below you find links to studies that can give you more information.
onlinelibrary.wiley.com/doi...
doi.org/10.1038/s41586-020-...
ashpublications.org/blood/a...
ashpublications.org/blood/a...
ncbi.nlm.nih.gov/pmc/articl...
ncbi.nlm.nih.gov/pmc/articl...
A high AB correlates to increased odds of homozygous mutation (both genes of a pair are mutated). vs heterozy where only one of the pair is mutated. With both genes mutated AB is naturally higher since each pair has double the allele count.
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You're providing evidence that high AB is also correlated to germline mutation. Can you provide the text that offers that info? It would enlarge our understanding. It is suspected that the mutation may occur in-utero before birth, but germline would take this even earlier.
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Homozy correlates to better MR response to IFN, discussed in old posts. This is why we often see rapid reductions from high AB. But you note this can be the opposite and we see here this fast action is not assured, and may take time. Do you have text that notes this inverse correlation? (High AB-> less MR)
If the person has heterozygous mutation and a VAF that is constantly at 50% or above on repeated NGS, at least for various non-canonical MPL mutations, but not only, probably it applies to other non-canonical mutations than MPL, this could inform an exploration of whether that mutation is germline. While I cannot find right now the exact paper on germline mutations in ET where I read this information, the paper below is presenting a similar information.
The study below is mentioning VAF ~50% on repeated NGS as indicative of germline mutations:
"Following VAF over time is an efficient way to identify potential germline variants using data already collected for diagnostic and prognostic purposes."
ashpublications.org/blood/a...
You can do a scientific literature search with this information.
I am aware that for somatic mutations VAF% is linked to other outcomes, but one needs to make the distinction between somatic and germline mutations. There is a whole scientific literature on germline versus somatic mutations in MPNs, especially in essential thrombocythemia, and another search word would be hereditary thrombocytosis.
sciencedirect.com/science/a...
It might be more straightforward in PV where one mutation is accounting for most cases, but even there I could see literature on PV due to non-canonical JAK mutations.
I havnt read all your links but from my reading and listening to experts I would say that the first line of your reply covers it ie “the suspicion that it can suggest” as opposed to it being a fact. Ie could be /maybe.
There is a whole scientific literature beyond what you read that is clear on the fact that cancers, MPNs included, can be caused either by a somatic mutation (acquired during lifetime) or by a germline mutation (inherited from parents), or even both. And given that a genetic test done on the affected cells will not always offer the answer on whether the mutation is somatic or it is germline, especially when VAF is 50% or above at repeated NGS with heterozygous pathogenic mutations, then an investigation on whether the mutation is germline, that is inherited, can be done.
The study below is mentioning VAF ~50% on repeated NGS as indicative of germline mutations:
"Following VAF over time is an efficient way to identify potential germline variants using data already collected for diagnostic and prognostic purposes."
ashpublications.org/blood/a...
Nothing is 100% sure and shouldn't be. That is not how science works. Science is about progress, science is self-correcting, science is evolving and what was considered as applicable in the past can be corrected and sometimes disproved as science is advancing. And your readings and your experts (who, by the way, are humans and often give summaries of fields, not detailed accounts) will not cover all exisiting scientific literature and topics in MPNs. And the more science advances, the more genes are discovered, the more is learned. And more recent scientific literature found a whole range of non-canonical mutations, both MPL, but also JAK mutations, capable of inducing MPNs, mutations that are inherited. VAF is a guide in assessing whether these new mutations are germline or not. The surest way is to do NGS on other material than blood or bone marrow, as germline mutations can be found in the DNA of every cell in the body, unlike somatic mutations that can be found only in affected cells.
Of course, you can stay with what confirms your views, if that is more comfortable. That is not science, that is the human need to have control over our circumstances.
You wrote "Nothing is 100% sure and shouldn't be. That is not how science works". Really?, obviously and clearly some science things are 100% sure.
You also wrote ""And your readings and your experts (who, by the way, are humans and often give summaries of fields, not detailed accounts) will not cover all existing scientific literature and topics in MPNs.""
Thats quite an assumption your making , I think the experts (and I have listened to many of them over 14 years in consults and doc conferences) do give detailed accounts and cover all the REAL facts which are RELEVANT to us patients, I think the good ones know all the science but wisely filter out what is not definite and irrevelent.
Talking about relevant , we should remember what the posters original question was 🙂
Again, that is not how science works. Science is not a trial in a criminal court. Science tests hypotheses to see if there is support for a theory. Sometimes science might conclude said theory is not supported, only for this to change later when technology allows for better tools to test that theory. Science evolves, we deepen our understanding, so nothing is or should be 100%, because that would mean lack of expanding knowledge. We are not "set" in science.
Dogma led humanity to imprison and torture fellow humans who dared to point the Earth is round when the dogma said it was flat.
Given that I do research myself, I am yet to meet anyone who does research who says one explanation or theory covers everything in terms of knowledge. Especially in medicine, where we have so much more to learn.
Until helicobacter pylori was discovered, stomach ulcers were thought to be caused by stress. They aren't. H.pylori causes them. Until MRIs became available, we could not diagnose multiple sclerosis with precision (i.e., active regions, scarring, etc.).
Just in the past couple of years, one of the biggest theories on Alzheimer's was shown to be unsatisfactory, so researchers are back to the drawing board after a decade of considering the respective theory as explaining Alzheimer's.
alzheimers.org.uk/for-resea...
Science self-corrects. And it is good that it does.
Less than a decade ago, a big expert in MPNs was still claiming that testing for other mutations than JAK2 in MPNs is irrelevant and might not bring benefit. I am happy some people did not listen to that advice, as for CALR mutations there is some research progress, and so called triple negative MPNs are getting more attention and pathogenic genes are shown to be behind some of them.
In a study, 3% of the general population harboured JAK2 mutations, yet only ~3% of that 3% showed the disease. This means there are many factors at play that take things from having a somatic mutation to an actual illness. Also, a study done on a similar population in the same country using earlier data, when technology was not as advanced, found that only 0.1% of the population harboured JAK2 mutation.
ashpublications.org/blood/a...
ncbi.nlm.nih.gov/pmc/articl...
An "expert" told me with confidence it is impossible the mutation I have is germline, i.e. hereditary, that there is "no chance" I have hereditary illness. Yet I have a germline mutation and I do have a hereditary illness. And there are studies on my mutation and similar mutations, and most likely newer studies will expand knowledge. So understanding the fact that experts have very narrow fields and might miss relevant scientific literature outside their field is important.
There is a lot of research on mutations in cancers generally that is informative regarding MPNs, sometimes directly applicable to MPNs. And they get more money than MPNs.
Also, there is a whole world of research on VAF outside somatic mutations such as JAK2V617F. Part of that research is on germline mutations.
The response below, where someone explains the difference between somatic and germline mutations, and the meaning of VAF for each type of mutation, is quite good.
thank you for your interesting but quite frankly bizzare reply
I wrote that explanation because you seem to have a limited view on science, and you do go after those who do not share it. Also, a bit of disrespectful reply from you and some sexism, so it is wiser for me to block you out.
I do have a limited knowledge of science , but a lot about PV, this is a MPN forum not a science forum and once again I refer you back to the posters original question which asking if anyone had a similar experience with Pegasys.
A fairly straight forward and common question which has a fairly straight forward answer to it which doesnt need lots of science theories.
I am intrigued by your comment about me being sexist especially as I have no idea what sex you are and my comments are not in any ways sexist. I think your replies are becoming increasingly bizzare and it would be wise to stick to MPN matters, this is not a science forum
In the report below VAF: some quick takes of interest:
-"VAF" is used for various other cancer mutations, Quite reasonable, but we're so used to seeing it for just the ones we know that seeing it used another way is new to me.
-"Ideally, germline variants have VAF ∼ 0.5 (50%) if heterozygous or VAF ∼ 1.0 if homozygous ". This is consistent with our prior info that homozy in MPN mutations (Jak2 etc) follows this same pattern of higher VAFs. In contrast germlines tend to fully saturate the gene with mutated alleles, as TTA alluded, vs the in-between VAFs we see with our somatic mutations.
-Germline mutation reports for MPN are mostly case studies, with minimal clinical guidelines for MPNs.
-Determining whether a mutation is germline vs somatic is not always easy. "suspicion of a germline variant should be confirmed by testing true germline DNA" Implication is germline confirmation is expensive and not part of the basic tests.
I had a germline mutation found in my BMB at Dx, but it has no known prognostic significance per the report.
1.5 years isn’t that long for the interferons to work , I know one person on 180 for two years before he stopt venisecting
Have you considered combining with Jakafi? Some research suggests the combination of the two, even a lower dose of Peg could be effective. Ask your doctor
I will speak with my Doctor about the possibility of adding another drug. Thanks.
How have your blood counts changed in those 18 months? There is a strong correlation between allele reduction (MR) and blood count response, discussed in many old posts. Complete response (CHR) in all the three main counts, PLT, HCT, WBC increases the likelihood of MR. There also are exceptions of course.
Has your Dr done a full gene study (NGS)? This looks for other non-driver mutations. Some can reduce the odds of MR, also in old posts.
My numbers really haven’t changed that much in those 18 months. My WBC are still high but finally heading in the right direction since I increased the Pegasys. My platelets are finally close to normal but I am still getting a phlebotomy every 3 months. Thanks for your suggestions.
The stubborn HCT on IFN seems to show up often here. If more time doesn't help, the combo suggested by Luthorville could be worth a try, insurance permitting. Rux (Jakafi) might help with the priority of HCT and can by itself and with IFN also reduce the mutation.
Hi, I know it is disappointing that your on this drug to hopefully lower AB but I wouldn't put too much emphasis on the importance of lowering this number as there is no factual proof thus far of the significance of doing so. I've been on nothing but two aspirin a day with 3 month phlebotomies. Had a bone marrow a year ago and after 21 yrs. of a PV diagnose at age 45, It showed no progression, no other non-driver mutations, no increased fibrosis tissue and my AB was over 90%!! Like you I have very mild symptoms. Just be HAPPY that your symptoms are mild and enjoy life! I currently exercise daily (definitely helps) and started to drink more water which seems to be helping with bouts of fatigue. Best to you! Kerry
Interesting facts 👍
Hi ritaandscooter,
Three years ago you wrote : » So, I turned 60 last fall (considered high risk now) and was placed on low dose Pegasys interferon. I've only been on this drug for 2 months and have been doing well with no side effects ». Did you stop taking Pegasys ?
Yes, I had started Pegasys upon turning 60 and started out with a 45mg dose and felt initially okay until my ALT/AST numbers shot up to 4x what they should be. Went to 22.5 dose which dropped the ALT/AST but then started to have other bad side effects. I believe I have spoken about all this in many previous posts. The drug did not work for me.
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