Cut-off point for disease versus no disease for JAK2V617F mutation positive individuals

[Manouche]

« …Furthermore, a novel observation was that no individuals with a myeloproliferative neoplasm were found in cases with an allele burden below 2%, which may represent a cut-off point of disease versus no disease for JAK2V617F mutation positive individuals ».

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

[EPguy]

I've heard about the 2% number before, thanks for the ref that it likely came from.

In this separate part, I think 10% refers to -without hematological indications, and probably without symptoms.

<<those individuals harboring the mutation without overt signs of a myeloproliferative neoplasm. These individuals, who often have less than 10% mutation burden, may suffer from a latent form of myeloproliferative neoplasm>>

10% was also of interest in the ContinuationPV study for Besremi

In that ContiPV study they seem to consider 10% a cut off for "operational cure" with ability to discontinue therapy a factor.

<<A sizable proportion of patients with PV achieved operational cure after 5 years’ ropeginterferon alfa-2b treatment. Lower age and lower allele burden at baseline predicted allele burden <10% at 5 years>>

library.ehaweb.org/eha/2021...

So there are two "cutoffs" here, not clear how to figure that. Of course 2% is broadly better.

For allele vs MPN type, in the original post report, these figures are listed.

Allele:

No MPN - 3.1%

ET- 5.5%

PV - 5.9%

MF - 13%

This is different from most others where ET is roughly 20% and PV is over 50%, MF ~80%, figures that we've also seen in the Forum. I may be reading it wrong, but I'm curious why it is so different.

[Manouche in reply to EPguy]

Three cut-off points are worth remembering:

JAK2 < 0.8 % = no MPN ( in the absence of other mutation)

JAK2 < 2% means the patient doesn’t have an MPN which can be biologically or clinically diagnosed although it’s there.

JAK2 <10% : patients who had a cytoreductive (INF) treatment for 2 years and are phlebotomy free, are allowed to take some INF holidays for a few months, or a few years.

[EPguy in reply to Manouche]

Thanks for the clear info. Puts a good context on it all.

Do you have any thoughts on the unusually low alleles vs MPN type in the report? Per these, most untreated PLB free PV and ET could qualify for the conceptual INF holiday if JAK2 is the reference. I'm sure I miss something.

[Manouche in reply to EPguy]

Hi ETguy,Could you remind me which report you are referring to ? Untreated ET or PV is not equivalent to previously treated ET/PV.

[EPguy in reply to Manouche]

Sorry it is confusing. I refer to this paragraph from the report in your original post

<<JAK2V617F mutation burden increased across the severity of myeloproliferative neoplasm diagnoses (Figure 5A). Individuals with no hematologically proven myeloproliferative neoplasm had a median JAK2V617F mutation burden of 3.1% (2.5th–97.5th percentiles: 0.9–5.7%), individuals with essential thrombocythemia had a median JAK2V617F mutation burden of 5.5% (3.1–62%), individuals with polycythemia vera had a median JAK2V617F mutation burden of 5.9% (2.1–27%), while individuals with primary myelofibrosis had a median JAK2V617F mutation burden of 13% (6.9–24%); the trend test across the 4 groups showed P=3*10−4.>>

The median JAK2 values are much lower than we usually see. Likely I miss something, are you familiar with these numbers? All MPN's are under 10% which low enough to be one of the cut off values.

[Manouche in reply to EPguy]

The low JAK2 allele burden in the general population can’t be compared to symptomatic JAK2 patients diagnosed at hospital. This could be called a « recruitment bias ».

[EPguy in reply to Manouche]

It seems to suggest this is the value in MPN:

"...individuals with polycythemia vera had a median JAK2V617F mutation burden of 5.9%..."

Does that include the general population within that group? Likely I'm missing some context.

[Turfbeg]

Many, many thanks for continuing to inform us of all that's being researched and reported with regards to our MPNs. Best wishes for 2022, keep safe!

[Aldebaran25]

This is all very valuable for our understanding of disease progression. However, I have approached my MPN haematologist at Guy's about the issue of allele burden (mine was never determined), and their position is that there is not yet enough evidence on JAK2 allele burden as a predictor, as there are several other non-driver mutations that also come into play. So in the UK, at least at Guy's, determining allele burden is not standard practice.

[EPguy in reply to Aldebaran25]

Good info on Guy's. If one has only the single JAK2 would Guy's have the same position? Would be curious their opinion there.

[Manouche in reply to Aldebaran25]

It depends the medication PV patients are given at Guy’s. As far as I know the vast majority are taking HU. Same in the UK and Europe. Haematologists are right to say there’s no point checking the JAK2 progression for patients taking HU as HU has no effect on JAK2 beyond the first year.

[EPguy in reply to Aldebaran25]

Reading more carefully, the part "not yet enough evidence" and "determining allele burden is not standard practice" does not make sense to me and I suggest getting further opinions. Reason is it's quite possible this baseline (before any treatment) info will be very useful in the future as research is quickly accumulating these days. (see example below) For example if one decides to start INF, with its known driver allele benefits and possible non driver benefits, baseline is likely to be an important reference point for future decisions.

As Manouch says, if one expects to remain on HU, allele is not of great interest, it is likely to increase long term. (Continuation PV study was clear on this) But I expect may of us will want to take advantage of other present and future therapies for which having a baseline allele, including all non-drivers, will be important.

Here is an example of why we might care a lot about allele in the future (in my reply in this post). A therapy can affect a non driver mutation (but this requires having the baseline info):

<<In vitro analyses indicated Jakafi (ruxolitinib, Incyte) reduced single-mutant and double-mutant (TET with JAK2) colonies in JAK2-first patients, whereas single-mutant and double-mutant colonies were unchanged in TET2-first patients.>>

healthunlocked.com/mpnvoice...

[Aldebaran25]

thank you for your replies ETguy and Manouche, very useful considerations. I am currently on HU as you imagined so that allele burden may not be so relevant for now (my first year on drug treatment), but it certainly makes sense to establish one's baseline for the future. I will bring this up at my next appointment (in March). Unfortunately going on Pegasys may be challenging in my case as I suffer from skin sarcoidosis, and alphaIFN may make this worse. But as you mentioned, there may be new treatments on the way and having a full picture of the base line situation may be useful to assess future approaches. I will insist !

[Jynx93]

My allele burden says “of no significance” on my letter, whatever that means

[Manouche in reply to Jynx93]

It means your AB level has no clinical significance and no bearing on the treatment plan established by your haematologist