jak2 Exon 12 and besremi?

[gdpone]

Anyone have data or first hand exp with this mutation and besremi?

[hunter5582]

I have the JAKv617f mutation. Besremi has been the best treatment option I have tried, more effective and easier to tolerate than anything else. Perhaps others with Exon 12 will weigh in with their experience. I am doubtful that Exon 12 will be different than v617f. Our responses to the meds is more unique to each of us. It is doubtless due to a number of factors including other parts of the genome.

[gdpone in reply to hunter5582]

Thanks. Yeah I’m concerned over the v617f being homozygous vs heterozygous for Exon 12.

[EPguy in reply to gdpone]

v617f can be of either zygousity. Homozy v617f associates with higher VAF (mutation) level, at least partly because homozy means both genes of the relevant pair are the same. So with both mutated that inherently doubles the VAF count. Homozy v617f is especially responsive to IFN therapy, discussed on old posts. If the same applies to heterozy Exon 12, IFN may have less effect.

Have you found that Exon 12 is never homozy? Would be interesting.

I have v617f, 14% at Dx, so likely heterozy. IFN reduced it by almost half. So, if mine is in fact heterozy IFN worked well on VAF and also blood counts.

--

There is not much on Exon 2 vs IFN. This report had a comment:

"The subjects with severe iron deficiency and highest red blood cell counts were those with JAK2-Exon-12-mutant PV....The two patients with JAK2-Exon-12-mutated PV did not show improvement (with IFN) in degree of iron deficiency despite decreased phlebotomy."

ncbi.nlm.nih.gov/pmc/articl...

But a small cohort and young pts only.

--

Interesting that a search for Exon 12 polycythemia brings up a lot of reports from ca 2010. Usually points to low recent research activity. Not clear why.

[gdpone in reply to EPguy]

Ok that’s interesting I did not know some of that. Still learning only got my official diag last week.

Interestingly I am also youngish at 37. And what’s more interesting to me is the only reason I was referred to a hematologist was because I was on testosterone which spiked my numbers. My most recent numbers after stopping testosterone and having had only 300ml of blood let 2 weeks before are:

RBC 5.88

Hb 17.8

HCT 50.8

PLT 329

And looking back before starting testosterone and no blood letting numbers were similar of much lower. I will be getting a BMB this coming Friday and will tell the tale. Of course part of me is hoping somehow I have the mutation but none of the features of MPN lol. But I’m not so much in denial that it’s anything more than a dream until I get back the results.

But I feel like my previous results belay a very mild disease burden so far if I’m lucky.

If further testing shows little disease burden I may opt simply for occasional blood letting and aspirin.

[EPguy in reply to gdpone]

You should ask about getting a mutation (VAF) reading via blood. The BMB may include it but that is a painful way to get periodic VAF updates and the two methods are best not compared.

Is that HCT intended to read 45.8? Normally under 45 is the PV treatment goal as risk goes up quickly over this limit.

Do you have WBC counts? These can be high in PV.

[gdpone in reply to EPguy]

Yeah I will ask my MPN specialist when referred. And sorry no it’s 50.8 for HCT and 7.8 for WBC

[EPguy in reply to gdpone]

50.8 is high for PV. Unless it's an outlier your Dr should be working with you to get it down quickly. usually that means phlebotomy. Mine went down on its own just in time to avoid phlb, but I've taken cytoreduction meds since then, mostly for PLT.

[gdpone in reply to EPguy]

When you say high for PV you mean with or without treatment? Because that’s is without treatment. I am waiting to see my specialist before starting anything except aspirin. Interestingly my local hematologist didn’t do another blood letting which I thought was odd.

And keep in mind this is from coming off testosterone which raised it. Before that it was hovering around 48 to 49.

[EPguy in reply to gdpone]

HCT <=45 is the goal for PV pts. This is without regard to how it comes to be at this level. So if it's there without phleb or cytoreduction then no treatment is required for HCT. But if it's regularly above 45, then starting, increasing, or changing treatments is the normal action.

This ~2012 trial has been the basis for this practice, the hazard ratio was nearly 4:

"those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis"

pubmed.ncbi.nlm.nih.gov/232...

I believe the risk increased rapidly at any value over 45 in the detailed analysis.

You may see a range up to ~50 as normal in your lab report; this is generic for pts without PV. With PV the normal safe range is tighter.

With all that I agree it's odd your Hem has not been more aggressive to lower the HCT. I got along without only because my HCT was clearly declining just after my Dx.

[gdpone in reply to EPguy]

Ok yeah I had read that before so just wanted to clarify. Also to follow up with that last line, mine too is falling as the labs previously were higher at …

Rbc 6.19

Hb 18.1

hct 52.6

I’m guessing that is why they didn’t draw more blood out of me, even though I agree it’s still too high, but I suspect because I was on testosterone and stopped they want to see what it will be off it? No idea.

[EPguy in reply to gdpone]

That is a good trend. Mine went from over 50 to ~45 in a couple weeks. Possibly anunusual factor as you describe; I had long covid.

You likely have been thru reports like this:

"Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations"

academic.oup.com/biomedgero...

This probably explains your Dr's patience with the HCT. All the terms in that quote are right on the point for PV. But your baseline was still over 45 so you may still need reduction once it stabilizes.

This leads to a new observation that testosterone therapy is likely contra indicated for PV pts.

BTW you should request EPO test if you don't already have that. It's often low with PV at Dx while many Drs don't order it.

[gdpone in reply to EPguy]

Yeah EPO is 8 and Ferratin is 119 ng/ml

I’ve read testosterone can increase EPO though. Will be curious to see where everything goes once off testosterone. Also I was wondering if testosterone is inherently contradicted or not too. I tried testosterone therapy once before in like 2013 and had similar problems with my blood counts increasing. No idea if I had a mutation back then too or not.

[gdpone in reply to EPguy]

To follow up on this yeah my hematologist really has no clue. They didn’t even know it’s supposed to be kept below 45%. Spoke with them this morning and said because my numbers were in range it was ok.

[EPguy in reply to gdpone]

That is a poorly informed Dr and good excuse to look for another, best case of course is MPN specialist.

[gdpone in reply to EPguy]

Yeah luckily my future MPN office called today to get the ball rolling waiting on an appointment. I will basically only be using my hematologist for bloodwork.

[hunter5582 in reply to gdpone]

As you have been discussing, your HCT is dangerously high for someone with PV. The goal for a male is HCT<45% to reduce risk of thrombosis. This is a critical treatment goal. Therapeutic phlebotomy is the quickest way to control erythrocytosis.

While testosterone supplementation can cause erythrocytosis, the JAK2 mutation definitely causes it. In the presence of the JAK2 mutation with erythrocytosis, reducing the HCT to target is an important treatment goal, even if part of the issue is the testosterone treatment.

You may find these webinars helpful in building your base of knowledge. Suggest starting with MPN Molecular Biology. mpninfo.org/conferences/202...

Wishing you all the best moving forward.

[gdpone in reply to hunter5582]

Yeah I am aware I need to get it down but have no way to until my hema takes my blood. I would just go give blood but as I understand it I can’t anymore.

[hunter5582]

You do not necessarily need to go to hematology office for a therapeutic phlebotomy. I have mine done at a blood donor center with an order from my hematologist. They cannot use the blood but they can provide the service. Not all blood donor centers provide this service but several in my area do

[gdpone in reply to hunter5582]

Yeah I will call them to get one. Thank you.

[WeylandYutani]

Hi,

I got an Exon 12 mutation and I'm on a low dosage of Besremi for about 3 years now (50 µg / three weeks). Besremi works great for me without any issues or problems, all (!) numbers are within limits for about one year now, so I can't complain.

I also got some data / information from a French research team regarding Exon 12 and Besremi, but I have to check where I put them.

In case you have any further questions, just let me know.

Cheers!

[gdpone in reply to WeylandYutani]

Thank

You very good to hear. Also do you know what your allele burden was when diagnosed?

[WeylandYutani in reply to gdpone]

I have to check, but it was something between 20 and 25%.

[gvibes]

Hello,

I was diagnosed about 3.5 years ago with p-vera with one of the exon-12 mutations and have been on pegasys - interferon for 3 years. At one point I was at 135 mcg weekly which has been reduced to 45 mcg every other week. I am stable in hematological remission. Pegasys has worked well for me.

I have been treated by a local hematologist with an MPN expert at Weill Cornell in NYC. When I asked originally about treatment for exon 12 version of PV, he maintained that the data show that you treat the same as the larger v617f mutation group and my treatment has been in line with this.

The studies that have found a significant numbers of exon 12 patients have shown some differences in disease presentation (eg, higher hematorcrit, more normal whites and platelets). As EPguy said, there are papers by Linda Scott, Passamonti et al and others around 2008 to 2011. Papers seem to conclude to treat the same as v617f mutated patients.

During a routine blood test in late 2020, they found hematocrit in my blood at 67% (without symptoms). I had 8 phlebotomies in 2 weeks to bring it below 45%. At one of the phlebotomies, they had trouble drawing blood as it was thick. I think I was fortunate.

Good luck - go slow and be patient with interferon - reach out if you have questions.

[gdpone in reply to gvibes]

Thank you this is very helpful. And thanks to all who have reponded especially who are also Exon 12s. I’m very relieved to hear treatment works the same. And yeah hct that high is nuts. Glad you got it down.

And yeah I plan to ask my mpn specialist if I can start on 50mcg. I want to least highest dose to avoid side effects. Some of them sound worse than the disease. At least for me so far.

[WeylandYutani in reply to gdpone]

If I may note, I started on 50 as well and it took some time so see an effect, so be patient.

[gdpone in reply to WeylandYutani]

Yeah thank you I have read that when on very low doses it takes longer to show an effect up to a year. I am fine with that as so far my disease state seems relatively low. I think I can afford a few years of slow rowing. I am fortunate.

[EPguy in reply to gdpone]

to gdpone

The "worse than the disease" may be specific to my experience, which may be what you refer. And you're right. A Sjogren experience is likely to be way worse than PV. This is why IFN has a black box. With your low dose plan this rare outcome should be near impossible. Watch for any neurological events.

[gdpone in reply to EPguy]

I did see your case yes and I’m very …. well you know that really sucks. I wish words could change it. If it’s any bit of matter it’s that your case shows it’s nothing to play with. A very rare case but I think all of us here know that doesn’t exactly mean what we thought it meant.

It will have me watching for any side effects that could be AI related. I recently had a few AI tests unrelated but they were all clear thankfully. But based on your posts I will ask for more.

My main concerns are heart, kidney, and thyroid. I already have mild LVH and low side TSH. And my egfr are a bit on the low side for my age for my liking to be concerned with protecting them.

If my BMB biopsy shows zero fibrosis and low alelle burden, I may even forgo any treatment other than blood letting. Hard to say will know more soon.