Hi all - haven’t posted in a while, but looking to see if anyone has had an experience like mine. I was diagnosed Oct 2020 with a hct over 70, and went through a torturous 3-4 months of weekly phlebotomies to get it down. Got on Pegasys pretty quickly, first injection early November 2020. After some temporary bouts of high liver enzymes, I began increasing my dose very slowly from 45 mcg to 135 mcg, and Ive been at 135 mcg for around 6 months. My AB at diagnosis was 68.8 and I got another test recently after about 2 years and it remained stubbornly at 65. Not sure what my next steps are, but options are (1) combo therapy with rux/Jakafi, (2) remain on 135 for the time being to see if I make any headway, or (3) try to increase the pegasys dose even more. My phlebotomies have increased in duration from 4-6 weeks to around 7-10 weeks, platelets have come down almost into normal range around 480, and WBCs are nicely between 5 and 7 last few months. I also have a spleen that’s been stuck at about 20 cm. Any experiences or advice would be appreciated.
JAK2 Allele Burden On Pegasys: Hi all - haven’t... - MPN Voice
JAK2 Allele Burden On Pegasys
2 years isn’t that long on the Peg journey, some take that long to get Hct control without venisection. I see you are still venisecting. Others on the Peg journey have increased the Peg dose up to say 180 until venisection free and often later they can lower the dose and sometimes get low AB numbers. The thing with Peg is it can be a longer journey and it doesn’t work for everyone. From the veterans I know they say it is a minority that get complete remission ie can come off it for a while and very low AB. 0thers may have better stats but 5 years is not a unreasonable time on Peg to get the max benefit in terms of remission and minimal AB for those who respond well to it. Some don’t get much lowering of AB. Although I personally suspect lower AB is better I listened to a video recently by Dr V and he said it was still not clear what the significance of lowering was.
to be accurate what he actually said is that so far we don’t what it actually means yet
thank you for you reply, I have seen the tension in the literature about the AB and what it means. There are also some models that suggest a correlation between high AB and shorter time to overt post PV MF. What I told my specialist is I’d like to be proactive if possible to try and get some momentum. So I/we came up with options to try. I don’t necessarily want to pull the trigger too early though if I am being too impatient with it. At diagnosis, we decided 2 years in we would regroup and take another AB test. Interestingly, my LDH has dipped into normal range under 250 for the past 6 months to a year. So im trying to decide if I want to stick with status quo another 6 months to a year or make some changes.
My dad had PV that turned into post PV MF it seems like fairly quickly when I was a kid, and I’m trying to avoid going down same path. He died from complications when I was 10 - he was 51. Interferon and JAK inhibitors were not available to him in the 1980s and early 1990s.
all else being equal as Paul mentioned a dose increase might be worth a try, I know what you mean re parents , my father had PV in the 70’s, treated him with radio phosphorus P32 and converted to leukamia, we are lucky we have better if not great treatments and of course the internet
It sounds like maybe you could ask about increasing Pegasys dosage if you are having no side effects. Eliminating venesections is important according to the Interferon Godfather, Dr Silver.
I was at 56% when dx in 2016, rose to over 80% by March 2018 when I started Pegasys at 45 mcg. I had regular JAK2 tests and hence recorded a fall to c. 55% after a year and under 20% after 2 years. Took 120 mcg weekly to eliminate venesections after about 20 months. Got it as low as 10% but had to reduce dosage to 30 mcg every three weeks to protect my too low WBC.
My JAK2 now rising and I’m back to 45 mcg weekly, which is holding JAK2 at 28%.
I also have the TET2 mutation which can make Pegasys less effective, it blocks the pathways Pegasys uses with inflammation. Evidently smoking has a similar result.
I try to follow an anti inflammatory diet plus plenty of exercise since I figure that reducing inflammation might make Pegasys more efficacious. I think I’ve had a good response and only problem has been unable to maintain the right dosage level without WBC overkill.
I saw some of your past posts where you seemed to be dealing with same issues. Thank you for your reply, Paul.
Hi All,
I was reading the posts, while intending to ask the OP what, if any "non-driver" mutations they also had [if they had been tested for same], and your post reinforced that intent.
I have seen a number of references to the possibility that "non-driver" mutations [defined as other co-existing and possibly somewhat-contributory mutations, which are present in addition to the original JAK2 or other primary mutations seen as the direct causes of MPN's] may be associated with resistance to various therapies- especially, but not limited to INF.
They are evaluated by "Next-Gen Sequencing " tests- most often of bone marrow, but sometimes by peripheral blood as well.
I'm still awaiting word of my results from my 7/22 BM Bx- which just reminded me to consult back with my Heme/Onc MD to see what if anything they found, since the lab hasn't posted anything about them.
If you [Snook] haven't had the 'Next-Gen Sequencing' testing yet, this may be the optimal time to request it, as it may help to decide your next step in treatment adjustment.
Best,
PA
Hi PA, I had a BMB in March 2021 and no non driver mutations, and MF1. Perhaps there’s something beyond what NGS tests, but nothing that was found.
Most likely your NGS looked for all that are known to matter. I had NGS in late 2020, they looked for 54 alleles, I figured that must be all of them. But they are now looking at way more, I've seen up to 200. Some of these obscure ones show up in studies, but what it all means is mostly for the future I think.
Hi Snook,
Then it sounds like there's no specific reason why your disease process should be resistant to IFN, meaning that there is a decent chance that you will eventually respond to the IFN at your current dosage, or if you're willing to risk the possibility of increased side-effects, and your Heme/Onc agrees, maybe going ahead with [slowly] advancing your dosage.
I think adding a second agent like Jakafi is also an option, but for long-term treatment, IFN's alone still seem to be the best overall strategy.
Especially given the lower risk of secondary infections and/or malignancies vs. HU, Jakafi, etc.
Best,
PA
On average getting CHR (HCT, WBC, and PLT all in range) via IFN increases odds of allele reductions. It could be with more dose and time you'll get here. This post has detailed discussion of these thoughts. The reports also indicate no clear connection of dose to allele reductions. From one report here for the Besremi trial "Dosing level (derived 4-weekly dose of 500 µg) had no apparent impact on the achievement of an allele burden <10%"
healthunlocked.com/mpnvoice...
Also it's common to see the fastest allele reductions in the first two years, as in the Besremi trial results here, likely why your Dr chose to check at that time.
But these are all averages, and we can and do get unique responses for each of us.
There are some members on the combo IFN/Rux and a trial of it was promising. Rux is known for potential of spleen reductions, so your Dr may have proposed it for that reason.
good post, I am surprised that the drop in AB was not dose related , maybe Peg is slightly different but from reading of others experience dose makes a difference, also looking at the reduction in AB from 38 to 9 is good but not as much as I thought it would have been.
Also quite a low AB to start with, Dr Spivak is of the opinion AB under 50 indicates a easier MPN journey anyway.
I've posted a lot on this area, and as always more answers leads to more questions. here is a part of one post:
-For Jak 2 homozygous type mutation, AB reductions occur with low doses and don't improve with more. Heterozygous Jak 2 requires higher doses to get AB reductions. My basic understanding Homozy is both parts of DNA pair carry the mutation, heterozy has only one of the pair mutated. A trade off I recall is homozy tends to have higher AB and lower prognosis. We are not normally tested for this, but based on this result it seems anyone with homozy really needs to discuss INF.
and "We did not identify any predictors of clinical response or observe a relationship between the dose of PEG administered and the degree of clinical response. "
This was for PEG and/or possibly PegIntron.
healthunlocked.com/mpnvoice...
--
In this post the reports show a very strong consistent pattern of CHR with MR for any IFN-a. So the dose that gets CHR is 1st step to hope for MR, on average. But Homozy (related to the higher AB levels) responds best to lower doses, Heterozy (related to lower alleles) requires higher doses to get MR. But I can't find a clear reconciliation of the CHR benefit of MR to zygousity.
In my case, I near certainly have heterozy with a blood AB at Dx of 14%. But I am so far getting AB reduction (to 10%) on modest Bes doses, and good CHR. My Dr was surprised to see such reduction from a relatively low level as it seems harder to get these reductions vs the high starting levels. I think the NAC supplement could be helping, but of course no proof of that.
--
You're right that only a small portion got the lowest ABs on Bes. I am getting the impression that less than 2% is an important level to see the best benefits. Here is the actual report:
"At six years, 20.7% of patients in the ropeginterferon alfa-2b group (n=19) achieved a JAK2V617F allele burden of less than 1%"
ashpublications.org/ashclin...
the figure of 20% seems to ring a bell, and not wanting to sound negative but according to Dr Hasselbalch up to 40% of people who go on Peg will eventually drop out due to sides (hopefully less on Bes), so presumably the lucky ones will be 20% of the 60% who could tolerate it ie 12%. Hopefully the numbers are better than that and 12% is better than nothing. Peg/Bes is still the best of a fairly poor selection of drugs currently available and it would be my drug of choice currently.
Here is some clear data from the Ropeg trial. If these are comparable Bes is 10% while PEG in your note is 40% for a 4X difference. But HU is still 3X better than Bes in severe sides:
"In total, 13/127 patients (10.2%) in the ropeginterferon-alfa-2b arm and 4/127 (3.1%) in the control arm discontinued treatment due to drug-related adverse events, approximately half of which occurred during the first year (in 6/13 and 2/4 patients, respectively)."
again not trying to sound negative but it seems odd they chose patients with quite a low starting AB ie around 38%. As mentioned before Dr Spivak is of the view that those with AB below 50 are in for a easier ride. As one who is sceptical about big Pharma’s ethics I wonder if they chose “easier” patients for some reason as opposed to those with AB in the 90’s or even 100, just a question as opposed to a firm view.
»As one who is sceptical about big Pharma’s ethics I wonder if they chose “easier” patients for some reason as opposed to those with AB in the 90’s »
My JAK2 AB was 84 at diagnosis and is now 3.9 after only 3 years of Pegasys. So, « easier » patients could be those with higher AB…
Conclusion: never trust statistics! 🙂
Your experience is great, and 1st time I am aware of that big result. It also is consistent with the Homozy vs Heterozy concept, at 84% I think you near certainly had/have Homozy with its generally good AB reduction potential ie "« easier » patients are likely be those with higher AB…"
Did you see most that reduction in the 1st 2 years? (or was it more linear?)
As I noted my Dr seemed to agree my low starting point should be a bigger challenge for AB reductions.
Hi EPguy,
As you said earlier, a good hematological response is usually the most important factor to get a molecular response. After the first year of Pegasys (90>45>90>135mcg) the AB dropped to 49.9 from 83.8 at diagnosis. After 24 months (135mcg) the result was even better with a 11.4 AB. The third year (135> 112.5mcg) was easier to predict (3.9). Logically, the fourth year should see an AB around 1.5, etc…if I manage to keep the same Pegasys dose and the same hematological response… 🤞🏻
Here is an approx plot of your AB vs time. I added the year 4 guess, looks about right. A near best case experience.
Your dose was adjusted for CHR correct? Did you ever go past the min needed for CHR?
I had 4% / 6 months. If I assume (big assumption) that continues to 1 year it's 8% off 14%, close to your 11.4-3.9. Not scientifically relevant but interesting.
Thanks! It seems that comparing good responder and poor responder separately is also more relevant than adding them up. You can find here individual curves and jak2 response of 200 patients: ncbi.nlm.nih.gov/pmc/articl...
l've seen a version of this report. But I can't really figure it out. It seems directed to validating a mathematical model vs comparing empirical results. This sample has real data looking good but their prediction line not so. Others do match well.
It does seem to have valuable info, and I'd like to understand it better.
”As I noted my Dr seemed to agree my low starting point should be a bigger challenge for AB reductions”
Not necessarily. I’ve heard of a PV patient diagnosed with an JAK2 allele burden at 4% who managed to get an undetectable AB after 4 years of Pegasys (90mcg).
That's what we all want to get. Do you know how quickly this patient decreased per year?
The general responses are I assume averages, but for base line AB% vs MR benefit, I don't know any actual reports, only implications from the Homozy vs heterozy, these being well reported. But there is a contrasting part in one report (likely in a prior post) that considered low starting AB to be good for MR. But no data in it to see that result.
that’s a great result for you congratulations. I think I am still sceptical about the trial where the starting AB is 38%. Assuming Dr Spivak is correct (and I think he usually is) these are not the patients that need treatment the most. Similarly if I was big pharma trying to sell a drug (which is their goal) I think I would have patients in ther with starting AB in the 80/90/100 to show how impressive it is in showing a big drop in AB.
»if I was big pharma trying to sell a drug (which is their goal) I think I would have patients in ther with starting AB in the 80/90/100 to show how impressive it is in showing a big drop in AB »
It shows that most haematologist working for big pharma are honest scientists who don’t necessarily want big pharma to make big money.
I asked my Dr about trial bias in context of the very high doses used in the Ropeg trials. He said trials very often have higher doses than later clinical use because the researchers want better odds of success. And there may be bias leakage in wanting success for the sponsors. But good studies do their best to avoid selection bias.
For AB in particular, since allele was not an initial endpoint, it seems unlikely to have selection bias on that point for the ropeg trial.
There was a Rux study with a far higher baseline AB (~70-80% I think) But it likely was for MF with its usually higher ABs. I posted on it somewhere.
As far as I know, the level of Jak2 allele burden has never been a condition to get in a clinical trial for interferon. Besides, there’s no need for big pharma to impress anyone with an AB drop most prescribers don’t care about.
I agree on lack of AB criteria. Reduced burden was not even an endpoint at the start of the Ropeg trials. It's only starting to be a goal bec Drs are accepting it's possible to do (my Dr is now on board having this goal) Next step is figuring out what to do with this new ability. (IFN old timers, Silver group etc will say "I told you so")
As in this thread, Dr Spivak is consistent that lower AB is better and by extension Heterozy is preferable to Homozy. But the high AB levels are better suited for AB reductions via IFN. A conflict and contrast.
If true, then if the Ropeg trial had selected for example an even lower 20% AB baseline, they might have seen less satisfying results.
possibly but again I question lowering already low/lowish AB when really the priority work should be lowering AB in those with high readings. Hence it is in my opinion more important to see if the drug can do that.
Of course this whole discussion assumes that lower AB is advantageous and we should factor in very recent comment from Dr V that we don’t know what it means yet.
On a side note I have to say I am a bit disappointed that they don’t know what it means yet as it been around for ever.
As a low AB patient with a sometimes heavy symptom burden, I greatly hope to get to the very lowest ABs for possibly lower burdens. I feel that 2% or less is where the best benefits could show up. But in my version of Dr V's view, "what do we do with this newly proven ability?"
i take combo rx of Jakafi 40mg daily and Pegasys 135mcg weekly for 8 months already
my blood count in normal range since started the
no more phlebotomy too
That's a great real world result. I recall you've had trouble with blood counts before starting the combo, is that right?
yes I am.
my blood count goes up and still high even after Jakafi increased to 40mg
IMO, it’s a type of treatment which coud be worth trying with Snook37. Bi-therapies will the standard management of our conditions in the near future.
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