By 5 years, about 14% of patients have undetectable JAK2 mutations.

[Manouche]

« Now with this interferon tolerance improved, your abilities improve, response is excellent, and there is a potential for more. I highlighted in my presentation a molecular response. Molecular response is where you are decreasing the JAK2allele burden. That's the percent of cells in a sample of the patients that have mutations, and it goes down over time steadily. By 5 years, about 14% of patients have undetectable JAK2 mutations. People say, what does this mean? I can't tell you yet, but response prospects are that if we continue like this, and you can with this drug, then more patients will have molecular response and you may have a potential for disease modification. Fewer patients will have not just a blood clot risk, but also less of a transformation to myelofibrosis or acute myeloid leukemia, which are long term complications not too many people talk about. »

targetedonc.com/view/new-ag...

[mfh7]

Interesting article and consistent with my reading on the topic. I am currently seeing the author Dr V and have had two doses of Besremi under his care. Saw him yesterday for the first time since starting besremi. Platelets are declining which is good but still needed a phlebotomy for now as hematocrit still rising for now although seemingly at a slower pace than my pre Besremi experience. Dose will be increased to 200mcg for next dose and then to 300mcg for the next assuming there are no problems. Doc seems to think the need for phlebotomy can be eliminated soon but we shall see. No major side effects to date other than minor aches a couple of days following injection.

[EPguy in reply to mfh7]

If your Hb stays high, you could be a good candidate for rusfertide discussed here.

You're fortunate to be with one of the world's top MPN guys. At this point there should be 6 year data on Ropeg. There are some data on Pegasys that showed the allele benefit declining starting at year 6. Dr V seems well positioned to know about any 6 year Ropeg data. If you're also curious and comfortable asking, could you ask him about that?

[mfh7 in reply to EPguy]

I will ask next month when I see him. I was a little surprised he was moving me to 200 and then 300 mcgs so quickly but he said most people in the study he referenced were on 500mcgs most of the time. Obviously I would like to take the lowest dose possible but at this point I have to rely on the expert. I did ask generally about the possibility of reduction of allele burden and he said that is not the main purpose of Besremi at this point for me and that we are really focusing on getting my lab numbers normalized to avoid or lower the chances of a thrombotic event. He is of the opinion that continued Phlebotomies over time causes a variation in hematocrit that may further lead to thrombotic events in some patients. He indicated reduction in allele burden would be a bonus but implied he was not yet a believer in that effect even though he knows it has occurred. Like you I have read a lot about allele burden and progression but Dr v seems less concerned about that at least in my situation. This is my interpretation of what he said at any rate. He is definitely a big proponent of Besremi for my PV situation. Traditional treatment for me would have been 5 more years of phlebotomies until age 60 and then hydroxurea. With Besremi he thinks I can avoid phlebotomies very soon and my platelets are already dropping. For me my goal is to get my iron level back up to be able to jog again and not be so tired all the time and I think the prior 5 years of phlebotomies has contributed to my iron deficiency.

[EPguy in reply to mfh7]

Hunter has posted in detail on the iron problem. Too many or long duration of PLBs (phlebotomies) will often cause it, and finding a fix that cuts the PLBs is very useful. If that is a primary goal Rusfertide discussed here seems good for your future, if/when it's approved.

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Dr V's info on the dose matches this report; now that I'm taking it I relate to these numbers:

mpn-hub.com/medical-informa...

<<The median dose of ropeginterferon alfa-2b per treatment cycle (4 weeks) in the fifth year was 499 μg, compared with > 700 μg in Years 1 and 2>>

I'm getting a clear response on 50mcg at least to start. At 500 I'd probably be out of commission.

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Your info from Dr. V is a surprise to me. I would have expected him to cheer the allele feature more. What is your burden %? We've had posts here on studies showing worse outcomes when it's over 50%, but these did not study reducing it.

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There is a possible contradiction in his info as I see it. His report here has <<patients will have molecular response and you may have a potential for disease modification>> So he seems to care about it in general, and notes "less of a transformation" the context of allele. But as you say, each case is unique. It's true that Bes was FDA approved on its hematological benefits, and FDA did not pay attention to allele.

I vote for the "may have" part of his comment here and would like to be

on the good side of that possibly turning into "will have" as they

learn more.

--

His comments to you do match his quote here from 2019:

targetedonc.com/view/versto...

<<A case in point is in the interferon studies where there is a significant decrease in theJAK2allele burden, but it does not correlate with a hematological response, a bone marrow response, or preventing progression. This is all investigational at the moment; I do not use this in clinical practice.>> But 2019 is a long time ago in this field.

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You may also have seen this post here which I often reference. It's a retrospective showing INF benefits. I asked one of the authors about the retro aspect and he said its strong results should address at least some possible bias.

healthunlocked.com/mpnvoice...

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My Dr said having a max tolerated dose gets the max benefit from Bes, I read that as relating to allele at the time. But there is at least one report also discussed on the Voice that indicates some patients get good blood counts and allele on smaller doses, and increasing the dose had minimal added benefit for some. I can look for these in the Voice posts if it's helpful.

[Elizka in reply to EPguy]

I saw my HEMO today (Major University doctor.) His thinking is that the ideal protocol for Besremi is the lowest possible dose while maintaining normal blood counts. He believes higher doses could lead to more toxicity. He bases this on other drugs not experience with Besremi. I'm not at "normal" blood counts yet. My dose will be 100 mcg next week. Then, he wants me to hold at 100 for a month to see where things land. Not sure what I'll advocate for, but the possibility of stopping progression is important, not just normal blood counts.

[EPguy in reply to Elizka]

I agree, with near any drug, the lowest effective dose is best. Our conflicting info seems to be defining "effective". It's obviously holding bloods to good numbers. But with allele now an option should we add that benefit to "effective"?. If so a dose would be sized to improve allele along with hem numbers.

Problem is experts don't agree whether this new option of allele is worthy. And assuming it becomes so, getting results is often measured in years.

[mfh7 in reply to EPguy]

Thanks. This is all great info. I was also somewhat surprised when Dr v downplayed the possible benefit to allele burden but I suspect that in this clinical role he was trying to manage my expectations. We may not hear his true current opinion on the matter in this setting but I will try to get him to clarify. Separately I think Besremi dosing is likely still up in the air and they are trying to figure it out and depends on the patient but we shall see. Dr v seemed less concerned than me regarding the risk/benefit of increasing the dose. I am approaching it from a simplistic standpoint which is if I have an adverse effect I will ask to back down but would like to see what higher dose does to benefit my numbers and produce the molecular response. He did indicate that he wanted to increase my dose toimprove heomological response and appeared to drawing my focus from the allele burden thing. I think my burden is 40% if I recall per very recent bmb. Dr v didn’t seem concerned about progression based on my situation at this point and instead very much stressed mitigation of a thrombotic event as the main goal for now.

[EPguy]

Thanks as always for the references.

Some items I find of interest:

<< I would say 5-10% of patients in community settings are usually exposed to interferon...Usually, in clinical studies with prior versions of interferon is only about 3-5 years on average duration...That's why hydroxyurea chemotherapy by mouth is a typical choice and 9 out of 10 patients would be given hydroxyurea>> -This shows why we're recently seeing so many of us switching, older INF was not a long term solution.

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<<Fewer patients (on INF) will have not just a blood clot risk, but also less of a transformation to myelofibrosis or acute myeloid leukemia>> This of course really gets our attention.

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<< (Our natural) INF goes up when we have inflammation or an infection and that causes some flu type symptoms that people usually recognize easily when we talk about side effects of interferon>> So INF meds are doing what they are supposed to when we get these side effects. He says less frequent injections with pegylated INF means less frequent flu like episodes.

-

If you're on INF and still too high Hb, Rusfertide, a new agent in trials also known as PTG-300, may be combined:

<<there are some patients that are on interferon and still require too many phlebotomies, you add rusfertide to it and eliminate the need for phlebotomies>> This seems a better solution than adding HU to the mix.

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This matches some of our members' experiences, improved side effects <<For ropeginterferon, (Besremi) the side effects are classic interferon related but less common>>