I'm starting my Besremi journey as in a recent post. I realize that my user name may have been a distraction, since quite reasonably it suggested I have a Dx of ET. In fact my Dx is PV, by both my first Hem and my present MPN specialist.
I do have some features of each as I've discussed before. I liked the ET handle since I am sort of extra terrestrial, it looks nice and is at least in part descriptive.
My MPN specialist prefers to describe MPN as a continuum without rigid compartments and says that I have "MPN". He says this is the current trend in the field.
This continuum is presumably directed to the Jak2 allele since CALR, MPL, and triple Neg, are more likely to preclude PV. It also seems reasonable that a patient with untreated HCT in the mid 50's and up and Jak2 allele of 60+, for example, would be largely in the PV range of the continuum.
This continuum concept is described for example in these reports and others:
MPNs as a continuum or discrete disorders is an active debate. Not all see it the same way. Spivak and others do see ET - PV - MF as discrete disorders with phenotypic mimicry.
Thanks to genetic-driver mutation testing, clinicians know much more about myeloproliferative neoplasm (MPN) pathophysiology. Despite these advances, diagnosing MPNs remains difficult.
MPNs are unique disorders, but they share genetic mutations, can mimic each other’s phenotype, and may even evolve into one another.
Polycythemia vera is the most common MPN—the ultimate phenotypic expression of a JAK2 mutation—and also the MPN with the most threatening morbidity, thrombosis.
I expect this will become ore clear as we better understand the underlying genotypes for MPNs and how they ultimately lead to the different phenotypes. It does seem clear that the heterozygous mutations have a different expression than homozygous mutations, even when it is the same mutation (e.g. JAK2v617f). It is of note that this same distinction bears on the expression of other disorders like NF1. Quite fascinating.
Hopefully this will be better understood as more information emerges.
Dr Spivak seems to know his stuff, and is contrarian in this report regarding WHO recommendations for Dx PV. (similar to Dr Silver and INF, and he's finally getting agreement there)
In this report-
He suggests MF is not an actual disease category, this muddies the separate category concept, at least re MF, for me:
<<myelofibrosis per se is not a disease>>
--
He says PV is the most common MPN. I've read usually that ET is. This report, a bit old at 2014, matches my observation:
<<The combined annual incidence rates for PV, ET, and PMF were 0.84, 1.03, and 0.47 per 100,000>>
All driver mutations do the same thing, activate JAK2. this is new to me:
<<The MPN driver mutations (JAK2 V617F, MPL W515K/L, CALR) all do the same thing—constitutively activate JAK2>>
I make a connection here to Rux, Jak inhibitor. Rux puts a lid on Jak2, but does not go to the underlying mutations that are activating it. INF is supposed to do that.
In this part:
<<You also need to understand that very low level JAK2 mutations occur in the general population without phenotypic consequences—again, the consequence of host genetic variation>>
A Danish paper we discussed in a recent post had alleles as low as 0.009 having negative prognostic.
--
Hems are doing it wrong:
<<Unfortunately, in many patients—particularly women—the erythrocytosis is masked by an expanded plasma volume, and the only way to make the diagnosis is to do a red cell mass and plasma volume study. This test has been available for over 50 years and was standard of care, but the WHO decided to eschew it in favor of bone marrow histology, even though the Polycythemia Vera Study Group proved over 50 years ago that this doesn’t work.>>
Maybe that term "masked" here is the "masked PV"
If this Dx method is correct, then a BMB has less value and red cell mass etc should be standard in our Dx. That is definitely contrarian.
--
I have read that Homozy (both of a gene pair is mutated) tends to higher alleles than heterozy, and tends to worse outcomes. But INF works at lower doses for Homozy. Problem is I think this status is rarely checked.
--
Another interesting item:
<<All these mutations also increase plasma thrombopoietin, which if elevated long enough can cause myelofibrosis. >>
This suggests that reducing plasma thrombopoietin is really desirable. Seems quite specific and doable. Maybe there is work in this area?
--
A separate item is the patent they reference. It's a very long one, but in the claims it has this procedure for prognostic in PV:
<<measuring the gene products of PCNA, IFI30, TSN, CTSA, SMC4, CDKN1A, CTTN, SON, TIA1, and MYL9...predicting based on the total score calculated in (c) the likelihood of the indolent form of PV in the subject to transform to an aggressive form of PV>>
My guess is his patients get this gene panel to indicate whether their PV will stay innocent. My 54 part gene panel had none of these exact numbers.
Spivak has patented his own gene panel for MPNs. He does have some different views on MPNs and how to diagnose and treat them. He sticks to the physician credo "First do no harm." He was the first MPN Specialist I saw. He has retired from clinical practice after 47 years, but is still active in other areas in the MPN world. He very definitely has a strong preference for the IFNs over HU. He and Silver agree on that issue.
I always find Spivak's views informative and well reasoned. I also find comparing his views to other MPN experts to be very informative. Seeking to understand the different views expands the understanding of MPNs. I do not believe any one MPN expert has found the universal truth for all MPNs. I think we all benefit from exploring a range of different opinions.
Regarding the similarity in effect of JAK2, CALR, and MPL - they do all activate the JAK-STAT pathway, causing a gain of function. Understanding the molecular biology of MPN is expanding. Hopefully basic science research on this will ultimately lead to better treatments tailored to each patient's genetic profile.
If he is consistent, he does not normally do BMB for his patients. Is that possibly one reason you did not have one at the start? Likewise, did you get red cell mass and plasma volume?
Looking up the terms, I see the studies skew old, <2005. That is consistent with the use of chromium 51 described here
My 1st Hem said Chr 51 is no longer used in modern practice. With Dr Spivak's long career he would know of it quite well. More inclination to ask my MPN Dr his opinion.
A study the same year confidently states that with RCM there is no unique info and <<Furthermore, alternative methods of PV diagnosis, based on disease-specific biological markers as well as bone marrow histology, are now available.>>
All this leave us amateurs pulled many directions.
Agree on the rapidly increasing bio understandings. That's why I feel getting a full gene panel is good. But maybe they should include Dr. Spivak's set if the patent owner, Johns Hopkins, offers the license.
I have actually seen 5 different hematologists in 30 years. none have ever felt a BMB was needed.
1992ish - diagnosed with ET based on CBC and other blood work.
2013 - re-diagnosed with ET based on CBC and other blood work. Was actually PV at this point. Oops!
2018 - Saw MPN Specialist (Spivak). Said my blood work was clear - no BMB needed. Pointed out that I was actually PV back in 2013. Did check allele burden,
2018 - My old hematologist fired himself and referred me to a colleague with more blood disease experience. Said "Your health is more important than my ego."
2018 - Seeing new hematologist at same practice - no BMB recommended.
2019 - New MPN Specialist at Johns Hopkins when Spivak retires. No BMB needed until there is an apparent change in disease status. When we saw progression in thrombocytosis, we did recheck allele burden and did MPN Myeloid panel (NGS). Assessment was increased thrombocytosis due to iron deficiency. No need for BMB.
I have asked on several occasions about whether a BMB was indicated. Not a single hematologist, including two MPN Specialists, felt it was needed in my situation. I have to assume that after 30 years of thrombocytosis, there is some level of fibrosis present. Knowing how much would not change anything at this point. I have already moved to using a more aggressive treatment strategy because of the symptoms I was experiencing. I am content to follow the plan of doing a BMB when we see a change in symptoms that indicates a change in disease status.
Elevation in erythrocyte numbers HCT, RBC and HGB. Some of the elevated numbers actually predate 2013, but have more 2013 numbers available. Looking at older history, it appears that I progressed from ET to PV. Process likely began before 2013, but was clear in 2013 that the progression had occurred.
Dr. Spivak does state that RCM is a more accurate way to assess PV than HCT. However, he did not order it for me. Did not really need it in my case. The issue with HCT is that it is actually a fuzzy measure. It is affected by plasma volume which can throw assessment of the actual level of erythrocytosis off. There are things other than PV that can affect plasma volume/HCT (e.g. hydration). It is however, the standard now to use HCT to ssess PV status and set the therapeutic target. It is what my care team and I use to monitor my treatment interventions, along with the rest of the CBC/CMP.
It’s an interesting discussion. My doc seems to see it this way as well. I also saw another MPN specialist who strictly went by the WHO criteria and by that standard I didn’t have PV but rather ET. My current specialist says no doubt PV and my reg hematologist thinks the same. Two versus one I guess. I asked current specialist about the WHO criteria and he sort of hinted that it’s more suggestion than anything. Basically a bunch of smart dudes get in a room and some see it one way and others see it another but they ultimately have to come to a consensus and that becomes the new criteria. He thought the next meeting would likely change the criteria even further to perhaps include lower Hct max for PV diagnosis.
Interestingly enough the first time I went to my current specialist I went armed with a bunch of questions and data, all backed by Dr. Spivaks research. Turns out my doc was a pupil of Spivak and Spivak was his mentor. So I thought for sure he’d follow the phlebotomy protocol my reg hematologist was recommending but was shocked when he advocated for HU. He said the evidence was inconclusive if HU really caused progression of the disease or it was just the disease itself. Lo and behold I went the phlebotomy route for the next year but didn’t really go after it like I probably should and so not much changed with my levels. Recently saw the doc again and sure enough he was still in the HU camp. I asked about Besremi and he was ok with trying that. He’s never been a fan of interferons before this one but recognizes that Besremi shows promising results (he’s also friends with Professor Jean-Jacques Kiladjian who demonstrated the positive effects for Besremi in the Proud PV study). Dude knows everyone.
In the end I think all of these disorders are a little more nuanced than hey let’s just look at a chart and call it what it is based on a few select criteria. Currently looking into Besremi and my docs are trying to get it worked out with insurance (which is a joke). CVS denied it then approved it after an appeal only to now say that I’m not even in the system when the Specialty Pharmacy called to get my coverage. 🤦🏻♂️
Anyway, who knows. I was all jazzed about Besremi but now not too thrilled with all the warnings. Not real keen on what it can do to the liver, etc. So while yeah it’s technically not cytotoxic if definitely can create toxicities in your body. Might be a moot point anyway depending on how it works out with my insurance. Might just end up going with HU cause I’m too damn cheap to spend a boatload on Besremi, even if it could be better. 😆
Agree there is a lot of ambiguity in our journey. If I understand it right, HCT is the current standard vs RCM. But as Hunter has noted, HCT is not always a true reflection of red cell status.
Your specialist seems quite special.
In my experience, and many but not all others here, HU works well for its intended purpose, if one can tolerate it. My understanding re progression, there has been unconfirmed concern about leukemic progression but I've not seen such concerns for fibrosis. Is there a history of that concern? It's generally considered less leukemogenic than the older chemos where such links have been apparent.
My Rx started with CVS specialty till they found they weren't specialized enough. There are only three extra specialized pharmacies in US that can provide it I think.
Re PEG vs Besremi, is there a specific improved feature or result for Bes that your specialist notes vs PEG? I have posted on the diffs, but there's no hard evidence so far. Hearing an expert's opinion, esp one previously less oriented to INFs, would be interesting.
On the liver etc, the protocol calls for careful monitoring of these blood numbers as you start, and dose tritration as required, or as possible, for any negative trends. On the warnings, both HU and Bes have Black Box warnings, and HU's is plenty scary also.
Agree on the cost, if paying retail you would need to be a mini Bill Gates to pay. The company has a program for zero cost, but I think it's limited if you're on Medicare.
It sounds like you do have a good MPN Specialist. I see a doc at John's Hopkins who was also trained by Dr. Spivak. He sees things in a similar way but has differences as well. You are right about how the WHO criteria are created. They are consensus guidelines, not Holy Writ. The can a do evolve over time.
What I do really like is having docs who take a more nuanced view of MPN treatment. MPNs are not monolithic disorders. There is a wide range of views and different ways to approach treatment. Individualized care is really the best way to go.
Regarding HU vs IFNs, different docs have different views. Both are viable treatment options. Each has its own risk/benefit profile. The same is true for phlebotomy-only. Having tried all three, my xperience is that IFNs are the most effective and easiest to tolerate. However, that is my experience. Could be totally different for someone else. My needs may change and evolve over time. Hopefully our understanding and options will continue to improve.
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.
Self Introduction and new MPN website 
