I see so many posts where people discuss reduction in JAK2 allele burden. In particular how certain medications are responsible for that reduction. I know there has been a lot of discussion regarding the significance of a reduction.
My question is, has there been any consensus among the world renowned MPN specialists that a reduced allele burden matters? I have read some reports that suggest it does/will make a difference by stopping progression of the disease, but have also read other reports stating there is still not definitive proof.
For someone like me who has been sticking with phlebotomies and aspirin only and willing to deal with the side effects I experience vs taking some new pill/shot and taking a chance on new side effects that may be worse, I am having a hard time agreeing to go on any type of medication because I don't feel there is any concrete proof it would slow progression. To me, it seems the medications are more for helping people with side effects of the disease and to help control HCT & platelets.
Does anyone feel they have come across credible research that shows a particular medication absolutely slows progression and are there a significant number of MPN specialists that agree with this research?
Written by
LIGEBA
To view profiles and participate in discussions please or .
There is a body of research regarding Variant Allele Frequency and an emerging consensus that it does matter in terms of prognosis and symptom burden. However, this is not a black-and-white issue. There is not an absolute linear correlation and not all view this issue the same way. My MPN Specialist put it in a good way saying the a reduced allele burden is a good thing, we just cannot prove how good it is - yet.
My own view is that allele burden does matter. I believe that that preventing progression of the MPN should be a primary treatment goal and that reducing VAF is a valid biomarker. Note that progression of the MPN should be measured not just in terms of progression to MF/AML but also progression in the severity of symptoms. They both matter.
My own experience is that Besremi is the most effective and easiest to tolerate treatment that I have tried. I was intolerant of and refractory to hydroxyurea. The side effects of phlebotomy-induced iron deficiency were worse than the PV symptoms. I feel better and have fewer issues with symptoms on Besremi than before. In fact. I feel better now than I did 10 years ago. In addition, my VAF has been reduced from 38% to 10%. Note that in the year prior to starting on the interferons, my VAF had jumped from 26% to 38%. In the context of having a non driver mutation (NF1) in addition to JAK2v618f, this was a significant concern.
My experience with MPN treatments does not predict what will happen for anyone else. I have my own treatment goals, risk tolerance, and preferred method of treatment. I would encourage anyone making a decision about how to treat their MPN to be very clear about your own treatment goals, risk tolerance, and treatment preferences. The decision should be highly individualized.
This is one of the better recent summaries of the literature on the significance of allele burden. Hope you find this helpful.
Rux has recently explicitly been shown to improve progression in correlation to VAF response. For IFN there is no study that had this endpoint but the retrospective studies by the Silver Cornell MPN center have found similar benefits, if less directly. There have been many posts referencing these studies.
So there is enough info to point to this benefit. If your current Jak2 VAF is low then it's possible this benefit is less. What is your Jak2 VAF? But most studies seem to look at effect of reducing VAF rater than the effect of an existing pre-treatment VAF.
If your Jak2 is high and you're young, it's possible there is a greater benefit of lowering it.
In an older thread you noted having an additional PIM1 mutation and we discussed a possible benefit of Jak inhibitor. But this is conjecture.
For "absolutely slows progression" there is none. Rux will slow it per the reports, but mostly when there is MR (molecular response). Certain non-driver mutations make this less likely. ASXL1 being the one identified in the report above. Same for IFN, not everyone gets MR.
You're right all meds have risks. IFN in particular has a black box warning for severe ones as I have experienced, but these are rare.
Yes. I'm too wasted on Sjogrens right now to get all the details, but it had progression as an endpoint, I believe the 1st to look for that endpoint. And they found MR leads to better prog free survival. The best MRs got the best results. Various Non-drivers were a negative prognostic, ASXL esp.
2% VAF was the limit to hold zero progression. Sample size is modest.
It's different from the one in the thread link above; that looked to event free, so a wider view. I compared them as noted:
"Compare (the two studies) ... Similar results on MR vs bad events. So results are substantially reproduced, a big deal in science and thus a clinical benefit for MR (at least on Rux) is clear."
For all these posts the focus has been on events rather than level of misery, for which member shiftzz below is still suffering with a ~zero VAF.
I don’t think I see it saying 2% was the limit to hold zero progression. If you look at the discussion at the end it 18% of the patients achieved AB less than 2% and then it says “ attainment of molecular response MAY be a surrogate of disease modification”
that's all. Also as you say the number of patients was very small.
Thanks for posting it though especially as your not feeling so well, I hope you feel better soon
I don't see it in the text either. But the plot shows it clearly. DMR is defined as "as a confirmed VAF<2%." CMR = undetectable. So the green line shows zero progression with a cut-off of 2% and no hazard ratio. Small n is an issue, on the other side the very long duration, 12 years, is a plus.
The outcome for no MR is not good. Interesting they found no MR correlation to most elements of CHR, except WBC response.
Thanks for the concern, Sjo unfortunately is a dead end on getting better. Only agents in trials give hope.
Thank you for clarifying , I see what you mean its allegedly happy days for those with VAF of lesss than 2%. However there are a few things about this trial that dont quite sit well with me, the obvious one is low numbers of patients, fair enough, but if you look at the graph it shows that at 10 years 25% of the patients with PMR converted to MF and those with no response allegedly 65% converted to MF, those numbest are much higher than the average conversions rates to MF for those on meds or not on meds.
In the literature it says on average 5%-15% convert to MF at 10 years with 10% being the most common number quoted. Maybe I missed something but if I didnt there is something suspicious about those figures on the graph.
The Majic PV has a similar result here. Both have EFS start to fall at 4 years for PR pts. I posted on these similarities last year. But n is 10 at the end so as you say these are small samples.
I agree it the treatment looks worse than no treatment. In the Majic study, the worse outcomes seem strongly biased by pts with non-drivers, esp ASXL. But still the "all" category is unexpectedly bad vs other known data.
Another strangeness is duration of response. This limitation is seen in IFN studies also as I recall. See following reply for the plot.
Yes I think that’s it, the trials seem to be Hydroxy resistant patients , it’s good for some of those patients Rux made such a big difference to survival.
This is seen in many reports for IFN, Rux etc, complete response (CHR) is transient. By this, HU and/or IFN (27% of BAT pts were on IFN) completely stops working after just 3.5 years. We know this is way off.
But this trial, as most others for Rux, had only "patients resistant/intolerant to hydroxycarbamide". HU resistance has a hazard ratio of ~5-7 for EFS (or progression alone, not sure). I've posted on this in detail.
So we may be seeing a strong influence of HU resistance.
That would be great if that mysterious mutation goes away.
On the VAF, you're starting level is relatively low like mine. This is the plot of my experience, 14-5% to last test. It tracks the Bes trials with respect to the fast initial drop and slower rate later. Rux looks to have resumed the fall, but this is not enough data yet to know the rate assuming it continues.
History, Diagnosed 8 years ago, been on venesection and aspirin, then Hydroxy then migrated to Paga.
Pega took time to make a difference, about 3 years, I was injection Pega and having Hydroxy, then dropped Hydroxy , Pega was once weekly at 135, now Pega every 10 days.
My JAK2 was never really high, but dropped to 3% or so, then 2 and the last test there was no detectable JAK2 mutation.
Do I feel any better? Not really, I am still tired, but I am making some progress with losing weight, that may help.
I have not had a face to face with my consultant for 3 years, I still have blood tests every three months and then a telephone consultation. I suspect they are simply reducing my risks rather than managing my symptoms.
They are very pleased about my JAK2 mutations, but no mention of anything else..
You are right that there is no consensus on the clinical benefit of reducing JAK 2 VAF. Some doctors simply do not give a test for this number as they consider it not meaningful as of now. However, as others pointed out, a growing body of research suggests that VAF is correlated with disease progression and blood clot events. The problem is that the level of correlation is often not linear, meaning that some would have high VAF number but not serious symptoms, and some would have low or even zero vaf number but still has rather serious disease. It might also have something to do with mutations in other genes.
You note symptoms, which is our level of misery. I've got that to the max. And shiftzz above is still suffering with zero VAF. I agree the correlation of VAF to misery is not well addressed.
Another correlation is hematological response, this is the traditional criteria for studies. We do see most members feel better when blood counts are all controlled (often abbrev CHR). I know I did in my pre "Last Dose" era. A strong correlation found in various IFN studies has been CHR - VAF reductions(MR). Without CHR, MR is signif less likely.
The focus of these Rux reports (or at least our attn to them) has been events/progression vs MR. It would be good to know any symptom correlates.
Jeffreylohoff interestingly enough, I had many more bothersome symptoms when my VAF was lower. There really does not seem to be any rhyme or reason to this disease.
there is as far as I am aware no firm evidence lowering AB slows progression, I also believe there is no firm evidence any of the meds slow progression, if the evidence was definitely there I would imagine big pharma would be shouting it from the roof tops and logically we would all be taking that drug or drugs, so far that’s not happened.
It seems lowering AB MIGHT be beneficial but even Dr Silver said in a vid that although AB can be virtually zero and the patient APPEARS to be in remission if they do a BMB the MPN is still there.
Personally I think lower AB MAY be a good thing and I speculate low is likely better than high.
To drug or not drug is a big subject, pwersonally I went on Rux after about 7 years on venisection only, I became too iron deficient (not everyone does), I also had bad itching. I feel better on Rux and have no sides and my counts are good and allegedly my BMB last year was better than the 2017 pre Rux, I will take that for now but we are all different. Others do well wit Peg etc but some like EP Guy can have severe and occasionally permanent sides. It’s a matter of weighing up the risk benefit.
One separate likely reason for the silence on progression is the gov't approvals were based on studies than measured only blood response vs HU for example. I believe the drug Cos can't promote benefits that were not a basis for approval. If they said something like "It was x% better than HU for blood counts, that likely is allowed but not very good TV. For those of us that still watch old fashioned TV we see this sort of talk in drug ads.
Anyway Incyte is done with any new Rux promos, its patent is up in 2028.
The term “events” in this context refers to clinical complications or outcomes related to the disease, and myelofibrotic progression is part of the events.
I don’t think that’s the case, events are for example thrombotic issues etc , if you look at Clair Harrison’s paper on Rux 2023 I think it was she refers to event free survival and progression free survival as two different things.
"EFS (major thrombosis, hemorrhage, transformation, and death)" Describing progression as "transformation" makes it into an "event". It would be nice to have these events separately called out.
It’s seems progression is indeed classed as an event, you were correct, even the dictionary says a process can be described as an event. Personally I would interpret an event as something that happened fairly quickly whereas progression as we know can be decades, hey ho things aren’t always as they seem.
This plot is compelling and new to the forum. Do you have the report it's from?
It does get confusing when some studies report EFS, while others specify progression free survival. I can see ainslie's point that an "event" could be different from "progression" since one has a moment of occurrence while the other is a state of disease. As seems agreement here, it requires a definition in the report to know the intent for each term.
You're noting this report uses the inclusive meaning of "event".
One thing missing is the prognostic of a baseline VAF, this plot is typical of most in that they report the benefit of a change in VAF but no prognostic for the baseline value. It's reasonable for studies that follow a therapy intended to cause VAF change.
See my reply to Manouche , a process such as progression can be classed as an event according to the dictionary, seems wrong to me but that’s what the dictionary says.
I see it's a very recent oral presentation. Thanks as always for the finds.
The newest message here is having MR (reduced mutation) is beneficial without regard to how it gets there. This slide shows this strong effect for both IFN and BAT (largely HU). And another slide showing same for Rux (image above in this thread) . So all drugs have similar MR benefit. But MR on HU tends to be of shorter duration so the benefit will likewise be shorter.
One slide has "higher v617f was associated with higher risk of events". This may mean the state of VAF rather than a reduction of it. I've written often on this ambiguity. Implication is a pre-therapy VAF below "the current threshold" provides the benefit without any therapy.
One slide refers to this "current threshold for MR". In the Rux study this was 2%, but it's not clear what that is for this slide.
Another slide refers to the 6 year final follow up. I've posted before that they have not published the VAF/time plot past 5 years, a conspicuous absence. But info I can't find again showed a trend upward at 6 years, as seen with PEG studies. So they have reason to discuss other details, as they have. The best responders did not have this rising effect.
--
This presentation is evidence the new agent from Incyte (see thread below) that better targets v617f may be on the right track, reducing the mutation is really useful.
These all sound like very interesting questions for anyone attending the upcoming forums to ask the specialists. They may not know yet but hopefully understanding is gradually moving on as more patients have HR and/or MRs and more time passes.
Content on HealthUnlocked does not replace the relationship between you and doctors or other healthcare professionals nor the advice you receive from them.
Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked.
Allele burden reduction!
Good news re allele burden
Allele burden shock
JAK2 allele burden
